Formulations of a bruton&#39;s tyrosine kinase inhibitor

ABSTRACT

Described herein is the Bruton&#39;s tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including novel pharmaceutical formulations thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/034,353, filed Aug. 7, 2014, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

Described herein is the Bruton's tyrosine kinase (Btk) inhibitor1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(ibrutinib), including novel pharmaceutical formulations thereof, aswell as pharmaceutical compositions that include the Btk inhibitor andmethods of using the Btk inhibitor in the treatment of diseases orconditions that would benefit from inhibition of Btk activity.

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase (Btk), a member of the Tec family ofnon-receptor tyrosine kinases, is a key signaling enzyme expressed inall hematopoietic cells types except T lymphocytes and natural killercells. Btk plays an essential role in the B-cell signaling pathwaylinking cell surface B-cell receptor (BCR) stimulation to downstreamintracellular responses.

Btk is a key regulator of B-cell development, activation, signaling, andsurvival. In addition, Btk plays a role in a number of otherhematopoetic cell signaling pathways, e.g., Toll like receptor (TLR) andcytokine receptor-mediated TNF-α production in macrophages, IgE receptor(FcepsilonRI) signaling in Mast cells, inhibition of Fas/APO-1 apoptoticsignaling in B-lineage lymphoid cells, and collagen-stimulated plateletaggregation.

1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-oneis also known by its IUPAC name as1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-oneor 2-Propen-1-one,1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl-,and has been given the USAN name, ibrutinib. The various names given foribrutinib are used interchangeably herein.

SUMMARY OF THE INVENTION

Described herein is the Btk inhibitor1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(ibrutinib) (Formula (I)) (Compound 1):

including pharmaceutical formulations, and methods of uses thereof. Alsodescribed are pharmaceutically acceptable compositions of the Btkinhibitor, and methods of uses thereof1-((R)-3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,as well as the pharmaceutically acceptable salts thereof, are used inthe manufacture of medicaments for the treatment of diseases orconditions that are associated with Btk activity.1-((R)-3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-oneis an irreversible Btk inhibitor.

Also described herein are methods for preparing pharmaceuticalformulations of1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.Further described are pharmaceutical compositions that include the novelformulations and methods of using the Btk inhibitor in the treatment ofdiseases or conditions (including diseases or conditions whereinirreversible inhibition of Btk provides therapeutic benefit to a mammalhaving the disease or condition).

Thus, in one aspect, the present invention provides solid dispersionpharmaceutical composition comprising solid dispersed ibrutinib.

In another aspect, the present invention provides solid dispersionpharmaceutical composition comprising solid dispersed ibrutinib, and thesolid dispersed ibrutinib is spray-dried ibrutinib and the spray-driedibrutinib is as defined herein.

In yet another aspect, the present invention provides solid dispersionformulations comprising solid dispersion pharmaceutical compositions asdescribed herein, and a pharmaceutically acceptable carrier.

In one embodiment, the formulation is in a form of a tablet, a pill, acapsule, a powder, or a liquid.

In another embodiment, the formulation is for oral administration.

In yet another embodiment, the formulation is a modified releaseformulation, a controlled release formulation, a sustained releaseformulation, or an immediate release formulation.

In certain embodiments, the formulation or composition provides improvedpharmacokinetics (PK) properties as compared to the capsule formulation;and the capsule formulation comprises ibrutinib that is not in a soliddispersed composition. In one embodiment, the PK properties include drugexposure (Cmax), and area under the curve (AUC). In certain embodiments,the formulation or composition provides reduced PK variability ascompared to the capsule formulation.

In yet another specific aspect, the present invention provides methodsto treat diseases or conditions using the composition and formulation ofthe present invention.

Exemplary diseases or conditions include an autoimmune disease orcondition.

In one aspect is a solid dispersion pharmaceutical compositioncomprising solid dispersed ibrutinib, wherein ibrutinib is a compound offormula (I),

In one embodiment is a pharmaceutical composition, wherein the soliddispersed ibrutinib is a spray-dried ibrutinib composition. In anotherembodiment, the spray-dried ibrutinib composition comprises ibrutinibdispersed into one or more solubility enhancers. In a furtherembodiment, the solubility enhancer is a polymer matrix; and the polymermatrix comprises one or more polymers. In one embodiment, thespray-dried ibrutinib composition comprises 1-90% w/w ibrutinibdispersed into the polymer matrix. In yet another embodiment, thespray-dried ibrutinib composition comprises about 20% w/w ibrutinibdispersed into the polymer matrix. In a further embodiment, thespray-dried ibrutinib composition comprises about 50% w/w ibrutinibdispersed into the polymer matrix. In one embodiment, the spray-driedibrutinib composition comprises about 70% w/w of ibrutinib dispersedinto the polymer matrix.

In another embodiment, the spray-dried ibrutinib composition comprisesabout 80% w/w of ibrutinib dispersed into the polymer matrix. In yetanother embodiment, the polymer in the polymer matrix is a linearpolymer, a cross-linked polymer, a co-polymer, a graft polymer; or anycombination thereof. In one embodiment, the polymer in the polymermatrix is hydrophilic. In another embodiment, the polymer in the polymermatrix is a non-ionic polymer. In a further embodiment, the polymer inthe polymer matrix is hypromellose, copovidone, or povidone. In yet afurther embodiment, the polymer in the polymer matrix is an ionicpolymer. In one embodiment, the polymer in the polymer matrix is acellulose based polymer. In another embodiment, the polymer in thepolymer matrix is hydroxypropylcellulose acetate-succinate,hydroxypropyl methyl cellulose phthalate, or cellulose acetatephthalate. In one embodiment, the polymer in the polymer matrix ishydroxypropyl cellulose, or hydroxypropylmethyl cellulose. In anotherembodiment, the polymer in the polymer matrix is hydroxypropyl methylcellulose acetate. In yet another embodiment, the polymer in the polymermatrix is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). Ina further embodiment, the polymer has a molecular weight in a range ofabout 2,000 to about 500,000 daltons, about 100,000 to about 200,000daltons, about 200,000 to about 300,000 daltons, or about 400,000 toabout 500,000 daltons. In yet a further embodiment, the polymer inpolymer matrix is polyvinyl caprolactam—polyvinyl acetate—polyethyleneglycol graft copolymer (Soluplus®). In one embodiment, the polymer inpolymer matrix is polyvinylpyrrolidone/vinyl acetate co-polymer,optionally in combination with polyvinyl caprolactam—polyvinylacetate—polyethylene glycol graft copolymer (Soluplus®).

In one aspect is a solid dispersion formulation comprising a soliddispersion pharmaceutical composition described above and apharmaceutically acceptable carrier. In one embodiment, the soliddispersion formulation is in a form of a liquid formulation or a solidformulation. In another embodiment, the solid dispersion formulation isin a form of a powder, dry powder, or a lyophilized powder. In yetanother embodiment, the solid dispersion formulation is in a form of asuspension, a hydrogel, an emulsion, a liposome, or a micelle. In afurther embodiment, the solid dispersion formulation is in a form of anaqueous suspension. In yet a further embodiment, the solid dispersionformulation is in a form of an organic suspension.

In one aspect is a solid dispersion formulation comprising a soliddispersion pharmaceutical composition described herein and one or moreexcipients. In one embodiment, the excipient comprises present in anamount from about 10 to about 50% w/w. In another embodiment, theexcipient comprises cellulose. In yet another embodiment, the excipientcomprises lactose. In a further embodiment, the excipient compriseslactose; and lactose is present in an amount from about 5 to about 20%,about 10 to about 20%, or about 14 to about 19% w/w. In yet a furtherembodiment, the excipient comprises microcrystalline cellulose. In oneembodiment, the excipient comprises microcrystalline cellulose; andmicrocrystalline cellulose is present in an amount from about 20 toabout 30%, about 23 to about 28%, or about 24 to about 26% w/w. Inanother embodiment, the excipient comprises a disintegrating agent. In afurther embodiment, the excipient comprises croscarmellose sodium orsodium starch glycolate. In yet another embodiment, the excipientcomprises croscarmellose sodium; and croscarmellose sodium is present inan amount from about 3 to about 9%, about 4 to about 8%, or about 5 toabout 7% w/w. In one embodiment, the formulation comprises lactose,microcrystalline cellulose, and croscarmellose sodium. In anotherembodiment, the formulation comprises lactose, microcrystallinecellulose, and croscarmellose sodium; and lactose is present in anamount from about 5 to about 20%, about 10 to about 20%, or about 14 toabout 19% w/w; microcrystalline cellulose is present in an amount fromabout 20 to about 30%, about 23 to about 28%, or about 24 to about 26%w/w; and croscarmellose sodium is present in an amount from about 3 toabout 9%, about 4 to about 8%, or about 5 to about 7% w/w. In oneembodiment, the formulation further comprises one or more glidants. In afurther embodiment, the glidant is silica (colloidal silicon dioxide).In yet a further embodiment, the glidant is silica (colloidal silicondioxide); and silica (colloidal silicon dioxide) is present in an amountfrom about 0.5 to about 1.5%, about 0.7 to about 1.3%, or about 0.9 toabout 1.1% w/w. In one embodiment, the formulation further comprises oneor more lubricants. In another embodiment, the lubricant is magnesiumstearate or sodium stearyl fumarate. In one embodiment, the lubricant ismagnesium stearate; and magnesium stearate is present in an amount fromabout 0.1 to about 0.5%, or about 0.2 to about 0.3% w/w. In anotherembodiment is a solid dispersion formulation wherein the soliddispersion is in an amount from about 30 to about 65%, about 45 to about55%, about 50 to about 55%, or about 50 to about 54% w/w.

In one embodiment, the formulation comprises

-   -   a) about 49 to about 51% w/w of 50% active spray-dried        ibrutinib,    -   b) about 16 to about 18% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.2 to about 0.8% w/w of magnesium stearate;    -   and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 50% w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is hydroxypropyl methyl cellulose acetate        succinate (HPMCAS).

In another embodiment, the formulation comprises

-   -   a) about 52 to about 54% w/w of 20% active spray-dried        ibrutinib,    -   b) about 13 to about 15% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.4 to about 0.6% w/w of magnesium stearate;    -   and wherein the 20% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 20% w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is hydroxypropyl methyl cellulose acetate        succinate (HPMCAS).

In a further embodiment, the HPMCAS is medium grade HPMCAS.

In yet a further embodiment, the formulation comprises

-   -   a) about 49 to about 51% w/w of 50% active spray-dried        ibrutinib,    -   b) about 16 to about 18% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.2 to about 0.8% w/w of magnesium stearate;    -   and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 50% w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is polyvinyl caprolactam—polyvinyl        acetate—polyethylene glycol graft copolymer (Soluplus®).

In another embodiment, the formulation comprises

-   -   a) about 30 to about 50% w/w of the solid dispersion        pharmaceutical composition,    -   b) about 20 to about 25% w/w of an excipient mixture comprising        microcrystalline cellulose, colloidal silicon dioxide, sodium        starch glycolate, and sodium stearyl fumarate,    -   c) about 0.2 to about 0.8% w/w of sodium stearyl fumarate, and    -   d) about 25 to about 35% w/w of crospovidone.

In one embodiment, the formulation comprises

-   -   a) about 45 to about 48% w/w of 33% active spray-dried        ibrutinib,    -   b) about 20 to about 25% w/w of an excipient mixture comprising        microcrystalline cellulose, colloidal silicon dioxide, sodium        starch glycolate, and sodium stearyl fumarate,    -   c) about 0.2 to about 0.8% w/w of sodium stearyl fumarate, and    -   d) about 25 to about 35% w/w of crospovidone,        and wherein the 33% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising 33% w/w of        ibrutinib dispersed into a polymer matrix.

In yet another embodiment, the formulation comprises

-   -   a) about 30 to about 33% w/w of 50% active spray-dried        ibrutinib,    -   b) about 20 to about 25% w/w of an excipient mixture comprising        microcrystalline cellulose, colloidal silicon dioxide, sodium        starch glycolate, and sodium stearyl fumarate, such as Prosolv®        EasyTab,    -   c) about 0.2 to about 0.8% w/w of sodium stearyl fumarate, and    -   d) about 25 to about 35% w/w of crospovidone,        and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising 50% w/w of        ibrutinib dispersed into a polymer matrix.

In one embodiment, the formulation is in an oral dosage form containinga therapeutically effective amount of ibrutinib. In another embodiment,the formulation is in a form of a tablet, a pill, a capsule, a liquid, amodified release formulation, a controlled release formulation, asustained release formulation, an immediate release formulation, or apowder. In yet another embodiment is a pharmaceutical composition or thespray-dried formulation described herein, wherein the pharmaceuticalcomposition or formulation provides improved pharmacokinetics (PK)properties as compared to a capsule formulation comprising ibrutinibthat is not in a solid dispersed composition. In another embodiment is apharmaceutical composition or the spray-dried formulation describedherein, wherein the pharmaceutical composition or formulation provides2-25 fold increase in drug exposure as compared to a capsule formulationcomprising ibrutinib that is not in a solid dispersed composition. In afurther embodiment is a pharmaceutical composition or the spray-driedformulation described herein, wherein the pharmaceutical composition orformulation provides 3-20 fold increase in drug exposure as compared toa capsule formulation comprising ibrutinib that is not in a soliddispersed composition. In a further embodiment is a pharmaceuticalcomposition or the spray-dried formulation described herein, wherein thepharmaceutical composition or formulation provides reduced PKvariability as compared to a capsule formulation comprising ibrutinibthat is not in a solid dispersed composition.

In a further embodiment is a pharmaceutical composition or thespray-dried formulation described herein, wherein the capsuleformulation comprises:

-   -   a) about 42 to about 43% of ibrutinib that is not in a solid        dispersed ibrutinib composition,    -   b) about 4 to about 5% w/w of surfactant SLS®,    -   c) about 45 to about 46% w/w of microcrystalline cellulose,    -   d) about 6 to about 7% w/w of croscarmellose sodium, and    -   e) about 0.4 to about 0.5% w/w of magnesium stearate.

In one aspect is a method of treating a disease in a patient in need ofsuch treatment, comprising administering to the patient atherapeutically effective amount of a pharmaceutical composition orformulation described herein. In one embodiment is a method for treatingan autoimmune disease or condition comprising administering to a patientin need thereof a therapeutically effective amount of a pharmaceuticalcomposition or a formulation described herein. In one embodiment, theautoimmune disease is selected from rheumatoid arthritis or lupus. Inanother embodiment is a method for treating a heteroimmune disease orcondition comprising administering to a patient in need thereof atherapeutically effective amount of a pharmaceutical composition or aformulation described herein.

In another aspect is a method for treating a cancer comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition or a formulation describedherein. In one embodiment, the cancer is a B-cell proliferativedisorder. In one embodiment, the B-cell proliferative disorder isdiffuse large B cell lymphoma, follicular lymphoma or chroniclymphocytic leukemia. In one embodiment, the cancer is a B cellmalignancy. In one embodiment, the cancer is a B cell malignancyselected from chronic lymphocytic leukemia (CLL)/small lymphocyticlymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Celllymphoma (DLBCL), and multiple myeloma. In one embodiment, the cancer isa lymphoma, leukemia or a solid tumor. In one embodiment, the cancer isdiffuse large B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In another embodimentis a method for treating mastocytosis comprising administering to apatient in need thereof a therapeutically effective amount of apharmaceutical composition or a formulation described herein. In anotherembodiment is a method for treating osteoporosis or bone resorptiondisorders comprising administering to a patient in need atherapeutically effective amount of a pharmaceutical composition or aformulation described herein. In one embodiment is a method for treatingan inflammatory disease or condition comprising administering to apatient in need a therapeutically effective amount of a pharmaceuticalcomposition or a formulation described herein. In one embodiment is amethod for treating lupus comprising administering to a patient in needa therapeutically effective amount of a pharmaceutical composition or aformulation described herein. In another embodiment is a method fortreating a heteroimmune disease or condition comprising administering toa patient in need a therapeutically effective amount of a pharmaceuticalcomposition or a formulation described herein.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the presentdisclosure will become apparent to those skilled in the art from thisdetailed description. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described. All documents, or portions of documents, citedin the application including, but not limited to, patents, patentapplications, articles, books, manuals, and treatises are herebyexpressly incorporated by reference in their entirety for any purpose.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the extent applicable andrelevant.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. shows mean plasma concentration-time profiles of ibrutinibfollowing single oral dose administration of different ibrutinibformulations to fasted beagle dogs (Dose=140 mg) (Formulation A—capsuleformulation; Formulation B, C, and D—Spray-dried formulations).

FIG. 2. shows mean plasma concentration-time profiles of ibrutinibfollowing single oral dose administration of different ibrutinibformulations to fasted beagle dogs (Dose=140 mg) (Formulation A—capsuleformulation; Formulation E, F, and G—Spray-dried formulations).

FIG. 3. illustrates the dissolution of the solid dispersion tabletFormulations B, C, and D as compared to the capsule formulation(Formulation A).

FIG. 4. illustrates the dissolution of the solid dispersion tabletFormulations E, F and G as compared to the capsule formulation(Formulation A).

DETAILED DESCRIPTION OF THE INVENTION

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. It is to be understoodthat the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof any subject matter claimed. In this application, the use of thesingular includes the plural unless specifically stated otherwise. Itmust be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. In this application, theuse of “or” means “and/or” unless stated otherwise. Furthermore, use ofthe term “including” as well as other forms, such as “include”,“includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, but not limited to, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

The term “about” when used before a numerical value indicates that thevalue may vary within a reasonable range, such as within ±10%, ±5% or±1% of the stated value.

As used herein, the term “comprising” is intended to mean that thecompositions and methods, etc., include the recited elements, but do notexclude others. “Consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination for the intended use, but notexcluding elements that do not materially affect the characteristic(s)of the compositions or methods. “Consisting of” shall mean excludingelements not specifically recited. Embodiments defined by each of thesetransition terms are within the scope of this invention.

The term “acceptable” or “pharmaceutically acceptable”, with respect toa formulation, composition or ingredient, as used herein, means havingno persistent detrimental effect on the general health of the subjectbeing treated or does not abrogate the biological activity or propertiesof the compound, and is relatively nontoxic.

As used herein, the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a protein that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the protein, such as, for example, Btk.

As used herein, the term “partial agonist” refers to a compound thepresence of which results in a biological activity of a protein that isof the same type as that resulting from the presence of a naturallyoccurring ligand for the protein, but of a lower magnitude.

As used herein, the term “antagonist” refers to a compound, the presenceof which results in a decrease in the magnitude of a biological activityof a protein. In certain embodiments, the presence of an antagonistresults in complete inhibition of a biological activity of a protein,such as, for example, Btk. In certain embodiments, an antagonist is aninhibitor.

As used herein, “amelioration” of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

“Bioavailability” refers to the percentage of Compound 1 dosed that isdelivered into the general circulation of the animal or human beingstudied. The total exposure (AUC_((0-∞))) of a drug when administeredintravenously is usually defined as 100% bioavailable (F %). “Oralbioavailability” refers to the extent to which Compound 1 is absorbedinto the general circulation when the pharmaceutical composition istaken orally as compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of Compound 1in the plasma component of blood of a subject. It is understood that theplasma concentration of Compound 1 may vary significantly betweensubjects, due to variability with respect to metabolism and/or possibleinteractions with other therapeutic agents. In accordance with oneembodiment disclosed herein, the blood plasma concentration of Compound1 may vary from subject to subject. Likewise, values such as maximumplasma concentration (C_(max)) or time to reach maximum plasmaconcentration (T_(max)), or total area under the plasma concentrationtime curve (AUC_((0-∞))) may vary from subject to subject. Due to thisvariability, the amount necessary to constitute “a therapeuticallyeffective amount” of Compound 1 may vary from subject to subject.

The term “Bruton's tyrosine kinase,” as used herein, refers to Bruton'styrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Pat. No.6,326,469 (GenBank Accession No. NP_000052).

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition including a compound as disclosed herein required to providea clinically significant decrease in disease symptoms without undueadverse side effects. An appropriate “effective amount” in anyindividual case may be determined using techniques, such as a doseescalation study. The term “therapeutically effective amount” includes,for example, a prophylactically effective amount. An “effective amount”of a compound disclosed herein is an amount effective to achieve adesired pharmacologic effect or therapeutic improvement without undueadverse side effects. It is understood that “an effect amount” or “atherapeutically effective amount” can vary from subject to subject, dueto variation in metabolism of Compound 1, age, weight, general conditionof the subject, the condition being treated, the severity of thecondition being treated, and the judgment of the prescribing physician.By way of example only, therapeutically effective amounts may bedetermined by routine experimentation, including but not limited to adose escalation clinical trial.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. By way of example, “enhancing”the effect of therapeutic agents refers to the ability to increase orprolong, either in potency or duration, the effect of therapeutic agentson during treatment of a disease, disorder or condition. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of a therapeutic agent in the treatmentof a disease, disorder or condition. When used in a patient, amountseffective for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

The terms “inhibits”, “inhibiting”, or “inhibitor” of a kinase, as usedherein, refer to inhibition of enzymatic phosphotransferase activity.

The term “irreversible inhibitor,” as used herein, refers to a compoundthat, upon contact with a target protein (e.g., a kinase) causes theformation of a new covalent bond with or within the protein, whereby oneor more of the target protein's biological activities (e.g.,phosphotransferase activity) is diminished or abolished notwithstandingthe subsequent presence or absence of the irreversible inhibitor.

The term “irreversible Btk inhibitor,” as used herein, refers to aninhibitor of Btk that can form a covalent bond with an amino acidresidue of Btk. In one embodiment, the irreversible inhibitor of Btk canform a covalent bond with a Cys residue of Btk; in particularembodiments, the irreversible inhibitor can form a covalent bond with aCys 481 residue (or a homolog thereof) of Btk or a cysteine residue inthe homologous corresponding position of another tyrosine kinase.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

The term “prophylactically effective amount,” as used herein, refersthat amount of a composition applied to a patient which will relieve tosome extent one or more of the symptoms of a disease, condition ordisorder being treated. In such prophylactic applications, such amountsmay depend on the patient's state of health, weight, and the like. It isconsidered well within the skill of the art for one to determine suchprophylactically effective amounts by routine experimentation,including, but not limited to, a dose escalation clinical trial.

The term “subject” or “patient” as used herein, refers to an animalwhich is the object of treatment, observation or experiment. By way ofexample only, a subject may be, but is not limited to, a mammalincluding, but not limited to, a human.

The terms “treat,” “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition. The terms “treat,”“treating” or “treatment”, include, but are not limited to, prophylacticand/or therapeutic treatments.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as inhibition of Btk, in an assay that measures suchresponse.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

Pharmaceutical Compositions/Formulations

A pharmaceutical composition, as used herein, refers to a mixture ofCompound 1 with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to a subject. The compounds can be usedsingly or in combination with one or more therapeutic agents ascomponents of mixtures.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. Compound 1 and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g.Compound 1 and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

In some embodiments, amorphous Compound 1 is incorporated intopharmaceutical compositions to provide solid oral dosage forms, such aspowders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

As used herein, the term “solid dispersion” refers to the dispersion ofone or more active agents in a polymer matrix at solid state prepared bya variety of methods, including, but not limited to spray drying, themelting (fusion), solvent, or the melting-solvent method. Moreinformation on “solid dispersion may be found in “Pharmaceutical SolidDispersion Technology” Edited by Muhammad J. Habib (TechnomicPublishing).

As used herein, the term “spray-dried ibrutinib” refers to a soliddispersion comprising ibrutinib dispersed into a polymer matrix preparedby a spray drying process, such as rapidly removing the solvent from thesolution of ibrutinib and the polymer by, e.g., spraying the solutioninto a drying gas flow. Suitable solvents include polar organicsolvents, such as alcohols such as methanol, ethanol, n-propanol,isopropanol, and butanol; esters such as ethyl acetate and propylacetate; ketones such as acetone, methylethylketone and methyl isobutylketone; acetonitrile, tetrahydrofuran, toluene, methylene chloride, and1,1,1-trichloroethane.

As used herein, the term “1-90% active spray-dried ibrutinib” refers toa spray-dried ibrutinib composition comprising 1-90% w/w ibrutinib basedon the total weight of the composition.

As used herein, the term “50% active spray-dried ibrutinib” refers to aspray-dried ibrutinib composition comprising about 50% w/w ibrutinib.

As used herein, the term “20% active spray-dried ibrutinib” refers to aspray-dried ibrutinib composition comprising about 20% w/w ibrutinib.

As used herein, the term “polymer matrix” refers to compositionscomprising one or more polymers in which the active agent can bedispersed or included within the matrix.

As used herein, the term “% w/w” refers to the weight of the componentbased on the total weight of a composition comprising the component.

As used herein, the term “crystalline” refers to a solid that exhibitslong-range order in three dimensions of at least about 100 repeat unitsin each dimension.

As used herein, the term “amorphous” refers to a solid that does notexhibit any long range order in the positions of the atoms, and isintended to include not only solid which has essentially no order, butalso solid which may have some small degree of order, but the order isin less than three dimensions and/or is only over short distances.Crystalline and amorphous forms of a compound may be characterized bytechniques known in the art such as powder x-ray diffraction (PXRD)crystallography, solid state NMR, or thermal techniques such asdifferential scanning calorimetry (DSC).

Solid Dispersed Ibrutinib

In one aspect, the present invention provides solid dispersionpharmaceutical compositions comprising solid dispersed ibrutinib.

In one embodiment, the solid dispersed ibrutinib composition is aspray-dried ibrutinib composition.

In one embodiment, the spray-dried ibrutinib composition comprises aspray-dried form of ibrutinib which is prepared or formed by dispersionof ibrutinib into one or more solubility enhancers.

In one embodiment, the solubility enhancer is a polymer matrix.

In one embodiment, the spray-dried ibrutinib composition comprises 1-90%w/w of ibrutinib dispersed into the polymer matrix. In anotherembodiment, the spray-dried ibrutinib composition comprises 10-90% w/wof ibrutinib dispersed into the polymer matrix. In another embodiment,the spray-dried ibrutinib composition comprises 20-80% w/w of ibrutinibdispersed into the polymer matrix. In another embodiment, thespray-dried ibrutinib composition comprises 30-70% w/w of ibrutinibdispersed into the polymer matrix. In another embodiment, thespray-dried ibrutinib composition comprises 40-60% w/w of ibrutinibdispersed into the polymer matrix.

In a particular embodiment, the spray-dried ibrutinib compositioncomprises about 20% w/w of ibrutinib dispersed into the polymer matrix.

In another particular embodiment, the spray-dried ibrutinib compositioncomprises about 50% w/w of ibrutinib dispersed into the polymer matrix.

In a further particular embodiment, the spray-dried ibrutinibcomposition comprises 70% w/w of ibrutinib dispersed into the polymermatrix.

In a further particular embodiment, the spray-dried ibrutinibcomposition comprises 80% w/w of ibrutinib dispersed into the polymermatrix.

In one embodiment, the polymer in the polymer matrix comprises a linearpolymer, a cross-linked polymer, a co-polymer, a graft polymer; or anycombination thereof

In another embodiment, the polymer in the polymer matrix is hydrophilic.

In another embodiment, the polymer in the polymer matrix is a non-ionicpolymer.

Exemplary non-ionic polymers include hydroxypropylmethyl cellulose,polyvinylpyrrolidone, Plasdone, polyvinyl alcohol, poloxamer,polysorbate, polyvinylpyrrolidone/vinyl acetate co-polymer (PVP-VA) andpolyethyleneglycols (PEGs).

In another embodiment, the polymer in the polymer matrix ishypromellose, copovidone, or povidone.

In another embodiment, the polymer in the polymer matrix is an ionicpolymer.

In another embodiment, the polymer in the polymer matrix is a cellulosebased polymer.

In another embodiment, the polymer in the polymer matrix ishydroxypropylcellulose; hydroxymethylcellulose;hydroxypropylmethylcellulose (HPMC), methylcellulose polymer,hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylenehydroxyethylcellulose and/or carboxymethyl hydroxyethylcellulose, anacrylic polymer, such as acrylic acid, acrylamide, and maleic anhydridepolymers and copolymers; or a blend thereof; or mixtures thereof

In another embodiment, the polymer in the polymer matrix ishydroxypropylcellulose acetate-succinate, hydroxypropyl methyl cellulosephthalate, or cellulose acetate phthalate.

In another embodiment, the polymer in the polymer matrix ishydroxypropyl cellulose, or hydroxypropylmethyl cellulose.

In another embodiment, the polymer in the polymer matrix ishydroxypropyl methyl cellulose acetate. In one embodiment, the weightratio of ibrutinib and the polymer is about 1:1. In another particularembodiment, the weight ratio of ibrutinib and the polymer is about 1:4.

In a particular embodiment, the polymer in the polymer matrix ishydroxypropyl methyl cellulose acetate succinate (HPMCAS). In oneembodiment, HPMCAS is of grade L. In another embodiment, HPMCAS is ofgrade H. In a particular embodiment, HPMCAS is of grade M.

In another embodiment, the polymer has a molecular weight in a range ofabout 2,000 to about 500,000 daltons, about 10,000 to about 90,000daltons, about 20,000 to about 70,000 daltons, about 30,000 to about60,000 daltons, about 40,000 to about 50,000 daltons, or about 10,000 toabout 20,000 daltons, about 20,000 to about 30,000 daltons, about 30,000to about 40,000 daltons, about 40,000 to about 50,000 daltons, about60,000 to about 70,000 daltons, about 70,000 to about 80,000 daltons,about 80,000 to about 90,000 daltons, about 90,000 to about 100,000daltons, about 100,000 to about 150,000 daltons, about 150,000 to about200,000 daltons, about 200,000 to about 250,000 daltons, about 250,000to about 300,000 daltons, about 350,000 to about 400,000 daltons, about400,000 to about 450,000 daltons, or about 450,000 to about 500,000daltons.

In a particular embodiment, the polymer has a molecular weight of about20,000.

In a particular embodiment, the polymer has a molecular weight of about140,000.

In a particular embodiment, the polymer has a molecular weight of about320,000.

In another particular embodiment, the polymer in polymer matrix ispolyvinyl caprolactam—polyvinyl acetate—polyethylene glycol graftcopolymer (Soluplus®).

In another embodiment, the polymer in the polymer matrix ispolyvinylpyrrolidone/vinyl acetate co-polymer. In one embodiment, theweight ratio of ibrutinib and the polymer is about 1:2. In oneembodiment, the weight ratio of ibrutinib and the polymer is about 1:1.

In another embodiment, the polymer in the polymer matrix ispolyvinylpyrrolidone/vinyl acetate co-polymer and polyvinylcaprolactam—polyvinyl acetate—polyethylene glycol graft copolymer. Inone embodiment, the weight ratio of ibrutinib,polyvinylpyrrolidone/vinyl acetate co-polymer and polyvinylcaprolactam—polyvinyl acetate—polyethylene glycol graft copolymer isabout 1:1:1.

In another embodiment, solid dispersed ibrutinib composition and inparticular the spray-dried ibrutinib composition provides improvedpharmacokinetics (PK) properties, such as higher AUC and/or reducedvariability in the pharmacokinetics parameters among different subjects,as compared to the pure ibrutinib, and in particular, a crystalline formof ibrutinib.

In some embodiments, the spray dried ibrutinib composition is preparedby a process comprising spray drying a solution of ibrutinib and thepolymer in an organic solvent, such as acetone, acetonitrile, methanol,ethanol, n-propanol, isopropanol, butanol ethyl acetate, propyl acetate,tetrahydrofuran, methylene chloride, toluene, 1,1,1-trichloroethane andmethylethylketone, etc.

In some embodiments, provided is a process of preparing the spray driedibrutinib composition described herein, which process comprises spraydrying a solution of ibrutinib and the polymer in an organic solvent,such as acetone, acetonitrile, methanol, ethanol, n-propanol,isopropanol, butanol ethyl acetate, propyl acetate, tetrahydrofuran,methylene chloride, toluene, 1,1,1-trichloroethane andmethylethylketone, etc.

Solid Dispersed Formulations

In another aspect, the present invention provides solid dispersionformulations comprising a solid dispersion pharmaceutical composition asdescribed herein, and a pharmaceutically acceptable excipient.

In one embodiment, the formulation comprises a solid dispersed ibrutinibcomposition.

In one embodiment, the solid dispersed ibrutinib composition is aspray-dried ibrutinib composition.

In one embodiment, the spray-dried ibrutinib composition comprises aspray-dried form of ibrutinib which is prepared or formed by dispersionof ibrutinib into one or more solubility enhancers.

In one embodiment, the solubility enhancer is a polymer matrix.

In one embodiment, the spray-dried ibrutinib composition comprises 1-90%w/w of ibrutinib dispersed into the polymer matrix. In anotherembodiment, the spray-dried ibrutinib composition comprises 10-90% w/wof ibrutinib dispersed into the polymer matrix. In another embodiment,the spray-dried ibrutinib composition comprises 20-80% w/w of ibrutinibdispersed into the polymer matrix. In another embodiment, thespray-dried ibrutinib composition comprises 30-70% w/w of ibrutinibdispersed into the polymer matrix. In another embodiment, thespray-dried ibrutinib composition comprises 40-60% w/w of ibrutinibdispersed into the polymer matrix.

In a particular embodiment, the spray-dried ibrutinib compositioncomprises about 20% w/w of ibrutinib dispersed into the polymer matrix.

In another particular embodiment, the spray-dried ibrutinib compositioncomprises about 50% w/w of ibrutinib dispersed into the polymer matrix.

In a further particular embodiment, the spray-dried ibrutinibcomposition comprises about 70% w/w of ibrutinib dispersed into thepolymer matrix.

In a further particular embodiment, the spray-dried ibrutinibcomposition comprises about 80% w/w of ibrutinib dispersed into thepolymer matrix.

In one embodiment, the polymer in the polymer matrix comprises a linearpolymer, a cross-linked polymer, a co-polymer, a graft polymer; or anycombination thereof

In another embodiment, the polymer in the polymer matrix is hydrophilic.

In another embodiment, the polymer in the polymer matrix is a non-ionicpolymer.

Exemplary non-ionic polymers include hydroxypropylmethyl cellulose,polyvinylpyrrolidone, Plasdone, polyvinyl alcohol, Pluronics, Tweens andPolyethyleneglycols (PEGs)

In another embodiment, the polymer in the polymer matrix ishypromellose, copovidone, or povidone.

In another embodiment, the polymer in the polymer matrix is an ionicpolymer.

In another embodiment, the polymer in the polymer matrix is a cellulosebased polymer.

In another embodiment, the polymer in the polymer matrix ishydroxypropylcellulose; hydroxymethylcellulose;hydroxypropylmethylcellulose (HPMC), methylcellulose polymer,hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylenehydroxyethylcellulose and/or carboxymethyl hydroxyethylcellulose, anacrylic polymer, such as acrylic acid, acrylamide, and maleic anhydridepolymers and copolymers; or a blend thereof; or mixtures thereof

In another embodiment, the polymer in the polymer matrix ishydroxypropylcellulose acetate-succinate, hydroxypropyl methyl cellulosephthalate, or cellulose acetate phthalate.

In another embodiment, the polymer in the polymer matrix ishydroxypropyl cellulose, or hydroxypropylmethyl cellulose.

In another embodiment, the polymer in the polymer matrix ishydroxypropyl methyl cellulose acetate.

In a particular embodiment, the polymer in the polymer matrix ishydroxypropyl methyl cellulose acetate succinate (HPMCAS).

In another embodiment, the polymer has a molecular weight in a range ofabout 2,000 to about 100,000 daltons, about 10,000 to about 90,000daltons, about 20,000 to about 70,000 daltons, about 30,000 to about60,000 daltons, about 40,000 to about 50,000 daltons, or about 10,000 toabout 20,000 daltons, about 20,000 to about 30,000 daltons, about 30,000to about 40,000 daltons, about 40,000 to about 50,000 daltons, about60,000 to about 70,000 daltons, about 70,000 to about 80,000 daltons,about 80,000 to about 90,000 daltons, or about 90,000 to about 100,000daltons, about 100,000 to about 150,000 daltons, about 150,000 to about200,000 daltons, about 200,000 to about 250,000 daltons, about 250,000to about 300,000 daltons, about 350,000 to about 400,000 daltons, about400,000 to about 450,000 daltons, or about 450,000 to about 500,000daltons.

In a particular embodiment, the polymer has a molecular weight of about20,000.

In a particular embodiment, the polymer has a molecular weight of about140,000.

In a particular embodiment, the polymer has a molecular weight of about320,000.

In another particular embodiment, with respect to the formulation, thepolymer in polymer matrix is polyvinyl caprolactam—polyvinylacetate—polyethylene glycol graft copolymer (Soluplus®).

In one embodiment, the solid dispersion formulation is in a form of aliquid formulation or a solid formulation.

In another embodiment, the solid dispersion formulation is in a form ofa powder, dry powder, or a lyophilized powder.

In another embodiment, the solid dispersion formulation is in a form ofa suspension, a hydrogel, an emulsion, a liposome, or a micelle.

In another embodiment, the solid dispersion formulation is in a form ofan aqueous suspension.

In another embodiment, the solid dispersion formulation is in a form ofan organic suspension.

In one embodiment, the solid dispersed ibrutinib composition (includingibrutinib and the matrix) is present in the formulation in an amountfrom about 10 to about 90%, about 20 to about 80%, about 30 to about70%, about 40 to about 55% w/w of the formulation.

In another embodiment, the formulation comprises one or more excipients.

Exemplary excipients used in the nanoparticle formulation can be foundin “Handbook of Pharmaceutical Excipients” Rowe et al., editors, 7^(th)edition, Pharmaceutical Press. London, 2012.

In certain embodiments, the excipients are selected from diluents,disintegrating agents, or surfactants, or a combination thereof

In certain embodiments, the excipients are selected from a groupconsisting of a polymer, a copolymer, and an anionic surfactant.

In some embodiments, the diluent is selected from the group consistingof lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol,xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate,starches, modified starches, microcrystalline cellulose, microcellulose,and talc. In some embodiments the diluent is microcrystalline cellulose.In some embodiments, the disintegrating agent is selected from the groupconsisting of natural starch, a pregelatinized starch, a sodium starch,methylcrystalline cellulose, methylcellulose, croscarmellose,croscarmellose sodium, cross-linked sodium carboxymethylcellulose,cross-linked carboxymethylcellulose, cross-linked croscarmellose,cross-linked starch such as sodium starch glycolate, cross-linkedpolymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodiumalginate, a clay, or a gum. In some embodiments, the disintegratingagent is croscarmellose sodium. In some embodiments, the surfactant isselected from the group consisting of sodium lauryl sulfate, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,poloxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide. In some embodiments, the surfactant is sodiumlauryl sulfate.

In certain embodiments, the excipient is present in an amount from about10 to about 50% w/w.

In certain embodiments, the excipient comprises cellulose.

In one embodiment, the excipient comprises lactose.

In another embodiment, the excipient comprises lactose; and lactose ispresent in an amount from about 0 to about 80% w/w. In anotherembodiment, lactose is present in an amount from about 5 to about 20%,about 10 to about 20%, or about 14 to about 19% w/w. In a particularembodiment, lactose is present in an amount of about 14%, about 15%,about 16%, about 17%, about 18%, or about 19% w/w, or any range betweentwo of the values, end points inclusive.

In another embodiment, the excipient comprises microcrystallinecellulose.

In another embodiment, the excipient comprises microcrystallinecellulose; and microcrystalline cellulose is present in an amount fromabout 0 to about 80% w/w. In another embodiment, microcrystallinecellulose is present in an amount from about 20 to about 30%, about 23to about 28%, or about 24 to about 26% w/w. In a particular embodiment,microcrystalline cellulose is present in an amount of about 23%, about24%, about 25%, about 26%, or about 27% w/w, or any range between two ofthe values, end points inclusive.

In another embodiment, the excipient comprises croscarmellose sodium.

In another embodiment, the excipient comprises croscarmellose sodium;and croscarmellose sodium is present in an amount from about 3 to about9%, about 4 to about 8%, or about 5 to about 7% w/w. In a particularembodiment, croscarmellose sodium is present in an amount of about 4%,about 5%, about 6%, about 7%, or about 8% w/w, or any range between twoof the values, end points inclusive.

In another embodiment, the formulation comprises lactose,microcrystalline cellulose, and croscarmellose sodium.

In a particular embodiment, the formulation comprises lactose,microcrystalline cellulose, and croscarmellose sodium; and

-   -   lactose is present in an amount from about 5 to about 20%, about        10 to about 20%, or about 14 to about 19% w/w;    -   microcrystalline cellulose is present in an amount from about 20        to about 30%, about 23 to about 28%, or about 24 to about 26%        w/w; and    -   croscarmellose sodium is present in an amount from about 3 to        about 9%, about 4 to about 8%, or about 5 to about 7% w/w.

In another embodiment, the formulation further comprises one or moreglidants.

In another embodiment, the glidant is silica (colloidal silicondioxide).

In another embodiment, the glidant is silica (colloidal silicondioxide); and glidant or silica (colloidal silicon dioxide) is presentin an amount from about 0.5 to about 1.5%, about 0.7 to about 1.3%, orabout 0.9 to about 1.1% w/w. In a particular embodiment, silica ispresent in an amount of about 0.5%, 1%, or 1.5% w/w, or any rangebetween two of the values, end points inclusive.

In another embodiment, the formulation further comprises one or morelubricants.

In some embodiments, the lubricant is selected from the group consistingof stearic acid, calcium hydroxide, talc, corn starch, sodium stearylfumerate, stearic acid, sodium stearates, magnesium stearate, zincstearate, and waxes. In some embodiments, the lubricant is magnesiumstearate.

In another embodiment, the lubricant is magnesium stearate; andlubricant or magnesium stearate is present in an amount from about 0.1to about 0.5%, or about 0.2 to about 0.3% w/w.

In another embodiment, the solid dispersion of ibrutinib is in an amountfrom about 30 to about 65%, about 45 to about 55%, about 50 to about55%, or about 50 to about 54% w/w. In a particular embodiment, the soliddispersion is present in an amount of about 30%, 33%, 40%, 48%, 49%,50%, 51%, 52%, 53% or 54% w/w, or any range between two of the values,end point inclusive.

In a particular embodiment, the formulation (Formulation C) comprises

-   -   a) about 49 to about 51% w/w of 50% active spray-dried        ibrutinib,    -   b) about 16 to about 18% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.2 to about 0.8% w/w or about 0.2 to about 0.3% w/w of        magnesium stearate;    -   and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 50 w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is hydroxypropyl methyl cellulose acetate        succinate (HPMCAS).

In another particular embodiment, the formulation (Formulation D)comprises

-   -   a) about 52 to about 54% w/w of 20% active spray-dried        ibrutinib,    -   b) about 13 to about 15% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.4 to about 0.6% w/w of magnesium stearate;    -   and wherein the 20% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 20% w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is hydroxypropyl methyl cellulose acetate        succinate (HPMCAS).

In a particular embodiment, the HPMCAS is M grade HPMCAS.

In another particular embodiment, the formulation (Formulation B)comprises

-   -   a) about 49 to about 51% w/w of 50% active spray-dried        ibrutinib,    -   b) about 16 to about 18% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.2 to about 0.8% w/w or about 0.2 to about 0.3% w/w of        magnesium stearate;    -   and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 50 w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is polyvinyl caprolactam—polyvinyl        acetate—polyethylene glycol graft copolymer (Soluplus®).

In another embodiment, the formulation is in an oral dosage formcontaining a therapeutically effective amount of spray-dried ibrutinib.In some embodiments, the pharmaceutical composition comprises about 0.5mg to about 1000 mg of spray-dried ibrutinib.

In another embodiment, the formulation is in a form of a tablet, a pill,a capsule, a liquid, or a powder. In another embodiment, the formulationis in a form of a modified release formulation. In another embodiment,the formulation is in a form of a controlled release formulation, asustained release formulation, an immediate release formulation, anextended released formulation, a prolonged release formulation, targetedrelease formulation. In yet another embodiment, the formulation is in aform of a powder.

In a further embodiment, the spray-dried ibrutinib is in amorphous form.

In another embodiment, the pharmaceutical composition or formulationprovides improved pharmacokinetics (PK) properties as compared to thecapsule formulation (Formulation A); and the capsule formulationcomprises:

-   -   a) about 42 to about 43% w/w of ibrutinib,    -   b) about 4 to about 5% w/w of surfactant (Sodium Lauryl Sulfate)        SLS®,    -   c) about 45 to about 46% w/w of microcrystalline cellulose,    -   d) about 6 to about 7% w/w of croscarmellose sodium, and    -   e) about 0.4 to about 0.5% w/w of magnesium stearate.

In another embodiment, the pharmaceutical composition or formulationprovides 2-25 fold increase in drug exposure as compared to the capsuleformulation.

In another embodiment, the pharmaceutical composition or formulationprovides 3-20 fold increase in drug exposure as compared to the capsuleformulation.

In another embodiment, the pharmaceutical composition or formulationprovides reduced PK variability as compared to the capsule formulation.

In some embodiments, provided herein is a pharmaceutical formulation(Formulation C) for oral administration comprising:

-   -   a) about 49 to about 51% w/w of 50% active spray-dried        ibrutinib,    -   b) about 16 to about 18% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.2 to about 0.3% w/w of magnesium stearate;    -   and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 50 w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is hydroxypropyl methyl cellulose acetate        succinate (HPMCAS).

In some embodiments, provided herein is a pharmaceutical formulation(Formulation D) for oral administration comprising:

-   -   a) about 52 to about 54% w/w of 20% active spray-dried        ibrutinib,    -   b) about 13 to about 15% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.4 to about 0.6% w/w of magnesium stearate;    -   and wherein the 20% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising about 20% w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is hydroxypropyl methyl cellulose acetate        succinate (HPMCAS).

In some embodiments, provided herein is a pharmaceutical formulation(Formulation B) for oral administration comprising:

-   -   a) about 49 to about 51% w/w of 50% active spray-dried        ibrutinib,    -   b) about 16 to about 18% w/w of lactose,    -   c) about 24 to about 26% w/w of microcrystalline cellulose,    -   d) about 5 to about 7% w/w of croscarmellose sodium,    -   e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, and    -   f) about 0.2 to about 0.3% w/w of magnesium stearate;        and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising 50% w/w of        ibrutinib dispersed into a polymer matrix; and the polymer in        the polymer matrix is polyvinyl caprolactam—polyvinyl        acetate—polyethylene glycol graft copolymer (Soluplus®)

In some embodiments, provided herein is a pharmaceutical formulation fororal administration comprising:

-   -   a) about 30 to about 50% w/w of a spray-dried ibrutinib        composition described herein,    -   b) about 20 to about 25% w/w of an excipient mixture comprising        microcrystalline cellulose, colloidal silicon dioxide, sodium        starch glycolate, and sodium stearyl fumarate, such as Prosolv®        EasyTab;    -   c) about 0.2 to about 0.8% w/w of sodium stearyl fumarate, and    -   d) about 25 to about 35% w/w of crospovidone.

In some embodiments, provided herein is a pharmaceutical formulation fororal administration comprising:

-   -   a) about 45 to about 48% w/w of 33% active spray-dried        ibrutinib,    -   b) about 20 to about 25% w/w of an excipient mixture comprising        microcrystalline cellulose, colloidal silicon dioxide, sodium        starch glycolate, and sodium stearyl fumarate, such as Prosolv®        EasyTab,    -   c) about 0.2 to about 0.8% w/w of sodium stearyl fumarate, and    -   d) about 25 to about 35% w/w of crospovidone,        and wherein the 33% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising 33% w/w of        ibrutinib dispersed into a polymer matrix. In some embodiments,        the polymer in the polymer matrix is polyvinylpyrrolidone/vinyl        acetate co-polymer. In some embodiments, the polymer in the        polymer matrix is a mixture of polyvinylpyrrolidone/vinyl        acetate co-polymer and polyvinyl caprolactam—polyvinyl        acetate—polyethylene glycol graft copolymer, such as in a 2:1 to        1:2, e.g., 1:1 ratio.

In some embodiments, provided herein is a pharmaceutical formulation fororal administration comprising:

-   -   a) about 30 to about 33% w/w of 50% active spray-dried        ibrutinib,    -   b) about 20 to about 25% w/w of an excipient mixture comprising        microcrystalline cellulose, colloidal silicon dioxide, sodium        starch glycolate, and sodium stearyl fumarate, such as Prosolv®        EasyTab,    -   c) about 0.2 to about 0.8% w/w of sodium stearyl fumarate, and    -   d) about 25 to about 35% w/w of crospovidone,        and wherein the 50% active spray-dried ibrutinib is a        spray-dried ibrutinib composition comprising 50% w/w of        ibrutinib dispersed into a polymer matrix. In some embodiments,        the polymer in the polymer matrix is polyvinylpyrrolidone/vinyl        acetate co-polymer.

In another aspect the present invention provides formulations orcompositions as described herein; wherein the formulation is in a unitdosage form in a blister pack, and said blister pack comprises metal orplastic foil. In one embodiment, the formulation is Formulation B. Inanother embodiment, the formulation is Formulation C. In a furtherembodiment, the formulation is Formulation D.

In another embodiment is a package comprising one or more discreteblister pockets, wherein each blister pocket comprises a unit dosageform comprising formulations or compositions as described herein. In oneembodiment, the formulation is Formulation B. In another embodiment, theformulation is Formulation C. In a further embodiment, the formulationis Formulation D.

In one embodiment, a kit is provided which contains a multiplicity oforal dosage forms, such as tablets or capsules, packaging such as a jarcontaining the oral dosage forms, and instructions for use to administerthe oral dosage forms in accordance with the method described herein.Unit dose packaging such as blister packs provide a useful way ofpackaging the oral dosage form of the formulations described herein, andin other embodiments embody a kit when combined with instructions foruse. In other embodiments, detailed product information are includedwith the instructions for use in the kit. Blister packaging isparticularly useful with solid oral dosage forms and is in furtherembodiments useful for alternate day dosing schedules for example. Inone embodiment, solid unit dosage forms of the formulations describedherein included in a blister pack with instructions to administer one ormore tablets or capsules on a daily basis so that the dosage of theformulations described herein are sufficiently administered. In anotherembodiment, solid unit dosage forms are included in a blister pack withinstructions to administer one or more tablets or capsules on analternate day basis so that the dosage per day is sufficientlyadministered.

Methods of Use

In one aspect, provided herein are methods for treating a patient byadministering Compound 1. In some embodiments, provided herein is amethod of inhibiting the activity of tyrosine kinase(s), such as Btk, orof treating a disease, disorder, or condition, which would benefit frominhibition of tyrosine kinase(s), such as Btk, in a mammal, whichincludes administering to the mammal a therapeutically effective amountof Compound 1, or pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, pharmaceutically acceptable prodrug, orpharmaceutically acceptable solvate.

In another aspect, provided herein is the use of Compound 1 forinhibiting Bruton's tyrosine kinase (Btk) activity or for the treatmentof a disease, disorder, or condition, which would benefit frominhibition of Bruton's tyrosine kinase (Btk) activity.

In some embodiments, amorphous Compound 1 is administered to a human.

In some embodiments, amorphous Compound 1 is orally administered.

In other embodiments, amorphous Compound 1 is used for the formulationof a medicament for the inhibition of tyrosine kinase activity. In someother embodiments, amorphous Compound 1 is used for the formulation of amedicament for the inhibition of Bruton's tyrosine kinase (Btk)activity.

In one aspect, provided herein is a method of treating cancer in amammal comprising administering to the mammal a pharmaceuticalcomposition or formulation described herein comprising Compound 1. Insome embodiments, the cancer is a B cell malignancy. In someembodiments, the cancer is a B cell malignancy selected from chroniclymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle celllymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiplemyeloma. In some embodiments, the cancer is a lymphoma, leukemia or asolid tumor. In some embodiments, the cancer is diffuse large B celllymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chroniclymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,plasma cell myeloma, plasmacytoma, extranodal marginal zone B celllymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma,mediastinal (thymic) large B cell lymphoma, intravascular large B celllymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, orlymphomatoid granulomatosis. In some embodiments, where the subject issuffering from a cancer, an anti-cancer agent is administered to thesubject in addition to one of the above-mentioned compounds. In oneembodiment, the anti-cancer agent is an inhibitor of mitogen-activatedprotein kinase signaling

In one aspect, provided herein is a method of treating an inflammatoryor an autoimmune disease in a mammal comprising administering to themammal a pharmaceutical composition described herein comprisingCompound 1. In some embodiments, the inflammatory disease is asthma,appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis,cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis,endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis,myelitis myocarditis, myositis, nephritis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis,pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis,vasculitis, or vulvitis. In some embodiments, the autoimmune disease isinflammatory bowel disease, arthritis, lupus, rheumatoid arthritis,psoriatic arthritis, osteoarthritis, Still's disease, juvenilearthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Graves' disease Sjögren's syndrome, multiple sclerosis,Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, orvulvodynia.

Articles of manufacture including packaging material, Compound 1 withinthe packaging material, and a label that indicates that Compound 1 isused for inhibiting the activity of tyrosine kinase(s), such as Btk, areprovided.

In a further aspect, provided herein is a method of treating anautoimmune disease in a mammal, comprising administering Compound 1 tothe mammal

In a further aspect, provided herein is a method of treating aheteroimmune disease or condition in a mammal, comprising administeringCompound 1 to the mammal

In a further aspect, provided herein is a method of treating aninflammatory disease in a mammal, comprising administering Compound 1 tothe mammal

In a further aspect, provided herein is a method of treating cancer in amammal, comprising administering Compound 1 to the mammal

In a further aspect, provided herein is a method of treating athromboembolic disorder in a mammal, comprising administering Compound 1to the mammal Thromboembolic disorders include, but are not limited to,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, or deepvenous thrombosis.

In another aspect are methods for modulating, including irreversiblyinhibiting the activity of Btk or other tyrosine kinases, wherein theother tyrosine kinases share homology with Btk by having a cysteineresidue (including a Cys 481 residue) that can form a covalent bond withCompound 1, in a mammal comprising administering to the mammal at leastonce an effective amount of Compound 1. In another aspect are methodsfor modulating, including irreversibly inhibiting, the activity of Btkin a mammal comprising administering to the mammal at least once aneffective amount of Compound 1. In another aspect are methods fortreating Btk-dependent or Btk mediated conditions or diseases,comprising administering to the mammal at least once an effective amountof Compound 1.

In another aspect are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount ofCompound 1.

A further aspect are methods for the treatment of cancer comprisingadministering to the mammal at least once an effective amount ofCompound 1. The type of cancer may include, but is not limited to,pancreatic cancer and other solid or hematological tumors.

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof Compound 1. In a further embodiment of this aspect, the respiratorydisease is asthma. In a further embodiment of this aspect, therespiratory disease includes, but is not limited to, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma.

In another aspect are methods for preventing rheumatoid arthritis and/orosteoarthritis comprising administering to the mammal at least once aneffective amount of Compound 1.

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of Compound 1. Such inflammatory responses of the skin include,by way of example, dermatitis, contact dermatitis, eczema, urticaria,rosacea, and scarring. In another aspect are methods for reducingpsoriatic lesions in the skin, joints, or other tissues or organs,comprising administering to the mammal an effective amount of Compound1.

In another aspect is the use of Compound 1 in the manufacture of amedicament for treating an inflammatory disease or condition in ananimal in which the activity of Btk or other tyrosine kinases, whereinthe other tyrosine kinases share homology with Btk by having a cysteineresidue (including a Cys 481 residue) that can form a covalent bond withat least one irreversible inhibitor described herein, contributes to thepathology and/or symptoms of the disease or condition. In one embodimentof this aspect, the tyrosine kinase protein is Btk. In another orfurther embodiment of this aspect, the inflammatory disease orconditions are respiratory, cardiovascular, or proliferative diseases.

In any of the aforementioned aspects are further embodiments in whichCompound 1 is (a) systemically administered to the mammal; (b)administered orally to the mammal; (c) intravenously administered to themammal; (d) administered by inhalation; (e) administered by nasaladministration; or (f) administered by injection to the mammal; (g)administered topically (dermal) to the mammal; (h) administered byophthalmic administration; or (i) administered rectally to the mammal

In any of the aforementioned aspects are further embodiments comprisingsingle administration of Compound 1, including further embodiments inwhich Compound 1 is administered (i) once; (ii) multiple times over thespan of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of Compound 1, including further embodiments inwhich (i) Compound 1 is administered in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) Compound 1 isadministered to the mammal every 8 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of Compound 1 is temporarily suspended or the dose ofCompound 1 being administered is temporarily reduced; at the end of thedrug holiday, dosing of Compound 1 is resumed. The length of the drugholiday can vary from 2 days to 1 year.

In some embodiments, in any of the embodiments disclosed herein(including methods, uses, formulations, combination therapy, etc.),Compound 1, or a pharmaceutically acceptable salt or solvate thereof,is: optically pure (i.e. greater than 99% chiral purity by HPLC). Insome embodiments, in any of the embodiments disclosed herein (includingmethods, uses, formulations, combination therapy, etc.), Compound 1, ora pharmaceutically acceptable salt or solvate thereof, is replaced with:a) Compound 1, or a pharmaceutically acceptable salt or solvate thereof,of lower chiral purity; b)1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,or a pharmaceutically acceptable salt or solvate thereof of any opticalpurity; or c) racemic1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,or a pharmaceutically acceptable salt or solvate thereof.

In any of the embodiments disclosed herein (including methods, uses,formulations, combination therapy, etc.), amorphous Compound 1 is used.In any of the embodiments disclosed herein (including methods, uses,formulations, combination therapy, etc.), amorphous Compound 1 is used.In any of the embodiments disclosed herein (including methods, uses,formulations, combination therapy, etc.), amorphous Compound 1 is used;and the amorphous compound is in the spray-dried form.

In some embodiments, in any of the embodiments disclosed herein(including methods, uses, formulations, combination therapy, etc.),Compound 1, or a pharmaceutically acceptable salt thereof, is replacedwith an active metabolite of Compound 1. In some embodiments, the activemetabolite is in a crystalline form. In some embodiments, the activemetabolite is in an amorphous phase. In further embodiments themetabolite is isolated. In some embodiments, in any of the embodimentsdisclosed herein (including methods, uses, formulations, combinationtherapy, etc.), Compound 1, or a pharmaceutically acceptable saltthereof, is replaced with a prodrug of Compound 1, or a deuteratedanalog of Compound 1, or a pharmaceutically acceptable salt thereof

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the presentdisclosure will become apparent to those skilled in the art from thisdetailed description. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described. All documents, or portions of documents, citedin the application including, but not limited to, patents, patentapplications, articles, books, manuals, and treatises are herebyexpressly incorporated by reference in their entirety for any purpose.

The diverse roles played by Btk signaling in various hematopoietic cellfunctions, e.g., B-cell receptor activation, suggests that smallmolecule Btk inhibitors, such as Compound 1, are useful for reducing therisk of or treating a variety of diseases affected by or affecting manycell types of the hematopoetic lineage including, e.g., autoimmunediseases, heteroimmune conditions or diseases, inflammatory diseases,cancer (e.g., B-cell proliferative disorders), and thromboembolicdisorders. Further, irreversible Btk inhibitor compounds, such asCompound 1, can be used to inhibit a small subset of other tyrosinekinases that share homology with Btk by having a cysteine residue(including a Cys 481 residue) that can form a covalent bond with theirreversible inhibitor.

In some embodiments, Compound 1 can be used in the treatment of anautoimmune disease in a mammal, which includes, but is not limited to,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still'sdisease, juvenile arthritis, lupus, diabetes, myasthenia gravis,Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren'ssyndrome, multiple sclerosis, Guillain-Barré syndrome, acutedisseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonussyndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome,aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture'ssyndrome, idiopathic thrombocytopenic purpura, optic neuritis,scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu'sarteritis, temporal arteritis, warm autoimmune hemolytic anemia,Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet'sdisease, chronic fatigue, dysautonomia, endometriosis, interstitialcystitis, neuromyotonia, scleroderma, and vulvodynia.

In some embodiments, Compound 1 can be used in the treatment of aheteroimmune disease or condition in a mammal, which include, but arenot limited to graft versus host disease, transplantation, transfusion,anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs,foods, insect poisons, animal hair, animal dander, dust mites, orcockroach calyx), type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, and atopic dermatitis.

In some embodiments, Compound 1 can be used in the treatment of aninflammatory disease in a mammal, which includes, but is not limited toasthma, inflammatory bowel disease, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

In yet other embodiments, the methods described herein can be used totreat a cancer, e.g., B-cell proliferative disorders, which include, butare not limited to diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In further embodiments, the methods described herein can be used totreat thromboembolic disorders, which include, but are not limited tomyocardial infarct, angina pectoris (including unstable angina),reocclusions or restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischemia, peripheral arterial occlusive disorders,pulmonary embolisms, and deep venous thromboses.

Hematological Malignancies

Disclosed herein, in certain embodiments, is a method for treating ahematological malignancy in an individual in need thereof, comprising:administering to the individual an amount of Compound 1.

In some embodiments, the hematological malignancy is a non-Hodgkin'slymphoma (NHL). In some embodiments, the hematological malignancy is achronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL),high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, thehematological malignancy is follicular lymphoma (FL), diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom'smacroglobulinemia, multiple myeloma (MM), marginal zone lymphoma,Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, orextranodal marginal zone B cell lymphoma. In some embodiments, thehematological malignancy is acute or chronic myelogenous (or myeloid)leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, orprecursor B-cell acute lymphoblastic leukemia. In some embodiments, thehematological malignancy is chronic lymphocytic leukemia (CLL). In someembodiments, the hematological malignancy is mantle cell lymphoma (MCL).In some embodiments, the hematological malignancy is diffuse largeB-cell lymphoma (DLBCL). In some embodiments, the hematologicalmalignancy is diffuse large B-cell lymphoma (DLBCL), ABC subtype. Insome embodiments, the hematological malignancy is diffuse large B-celllymphoma (DLBCL), GCB subtype. In some embodiments, the hematologicalmalignancy is Waldenstrom's macroglobulinemia (WM). In some embodiments,the hematological malignancy is multiple myeloma (MM). In someembodiments, the hematological malignancy is Burkitt's lymphoma. In someembodiments, the hematological malignancy is follicular lymphoma (FL).In some embodiments, the hematological malignancy is transformedfollicular lymphoma. In some embodiments, the hematological malignancyis marginal zone lymphoma.

In some embodiments, the hematological malignancy is relapsed orrefractory non-Hodgkin's lymphoma (NHL). In some embodiments, thehematological malignancy is relapsed or refractory diffuse large B-celllymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL),relapsed or refractory follicular lymphoma (FL), relapsed or refractoryCLL, relapsed or refractory SLL, relapsed or refractory multiplemyeloma, relapsed or refractory Waldenstrom's macroglobulinemia,relapsed or refractory multiple myeloma (MM), relapsed or refractorymarginal zone lymphoma, relapsed or refractory Burkitt's lymphoma,relapsed or refractory non-Burkitt high grade B cell lymphoma, relapsedor refractory extranodal marginal zone B cell lymphoma. In someembodiments, the hematological malignancy is a relapsed or refractoryacute or chronic myelogenous (or myeloid) leukemia, relapsed orrefractory myelodysplastic syndrome, relapsed or refractory acutelymphoblastic leukemia, or relapsed or refractory precursor B-cell acutelymphoblastic leukemia. In some embodiments, the hematologicalmalignancy is relapsed or refractory chronic lymphocytic leukemia (CLL).In some embodiments, the hematological malignancy is relapsed orrefractory mantle cell lymphoma (MCL). In some embodiments, thehematological malignancy is relapsed or refractory diffuse large B-celllymphoma (DLBCL). In some embodiments, the hematological malignancy isrelapsed or refractory diffuse large B-cell lymphoma (DLBCL), ABCsubtype. In some embodiments, the hematological malignancy is relapsedor refractory diffuse large B-cell lymphoma (DLBCL), GCB subtype. Insome embodiments, the hematological malignancy is relapsed or refractoryWaldenstrom's macroglobulinemia (WM). In some embodiments, thehematological malignancy is relapsed or refractory multiple myeloma(MM). In some embodiments, the hematological malignancy is relapsed orrefractory Burkitt's lymphoma. In some embodiments, the hematologicalmalignancy is relapsed or refractory follicular lymphoma (FL).

In some embodiments, the hematological malignancy is a hematologicalmalignancy that is classified as high-risk. In some embodiments, thehematological malignancy is high risk CLL or high risk SLL.

B-cell lymphoproliferative disorders (BCLDs) are neoplasms of the bloodand encompass, inter alia, non-Hodgkin lymphoma, multiple myeloma, andleukemia. BCLDs can originate either in the lymphatic tissues (as in thecase of lymphoma) or in the bone marrow (as in the case of leukemia andmyeloma), and they all are involved with the uncontrolled growth oflymphocytes or white blood cells. There are many subtypes of BCLD, e.g.,chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Thedisease course and treatment of BCLD is dependent on the BCLD subtype;however, even within each subtype the clinical presentation, morphologicappearance, and response to therapy is heterogeneous.

Malignant lymphomas are neoplastic transformations of cells that residepredominantly within lymphoid tissues. Two groups of malignant lymphomasare Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types oflymphomas infiltrate reticuloendothelial tissues. However, they differin the neoplastic cell of origin, site of disease, presence of systemicsymptoms, and response to treatment (Freedman et al., “Non-Hodgkin'sLymphomas” Chapter 134, Cancer Medicine, (an approved publication of theAmerican Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).

Non-Hodgkin's Lymphomas

Disclosed herein, in certain embodiments, is a method for treating anon-Hodgkin's lymphoma in an individual in need thereof, comprising:administering to the individual an amount of Compound 1.

Further disclosed herein, in certain embodiments, is a method fortreating relapsed or refractory non-Hodgkin's lymphoma in an individualin need thereof, comprising: administering to the individual atherapeutically-effective amount of Compound 1. In some embodiments, thenon-Hodgkin's lymphoma is relapsed or refractory diffuse large B-celllymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsedor refractory follicular lymphoma, or relapsed or refractory CLL.

Non-Hodgkin lymphomas (NHL) are a diverse group of malignancies that arepredominately of B-cell origin. NHL may develop in any organs associatedwith lymphatic system such as spleen, lymph nodes or tonsils and canoccur at any age. NHL is often marked by enlarged lymph nodes, fever,and weight loss. NHL is classified as either B-cell or T-cell NHL.Lymphomas related to lymphoproliferative disorders following bone marrowor stem cell transplantation are usually B-cell NHL. In the WorkingFormulation classification scheme, NHL has been divided into low-,intermediate-, and high-grade categories by virtue of their naturalhistories (see “The Non-Hodgkin's Lymphoma Pathologic ClassificationProject,” Cancer 49(1982):2112-2135). The low-grade lymphomas areindolent, with a median survival of 5 to 10 years (Horning and Rosenberg(1984) N. Engl. J. Med. 311:1471-1475). Although chemotherapy can induceremissions in the majority of indolent lymphomas, cures are rare andmost patients eventually relapse, requiring further therapy. Theintermediate- and high-grade lymphomas are more aggressive tumors, butthey have a greater chance for cure with chemotherapy. However, asignificant proportion of these patients will relapse and requirefurther treatment.

A non-limiting list of the B-cell NHL includes Burkitt's lymphoma (e.g.,Endemic Burkitt's Lymphoma and Sporadic Burkitt's Lymphoma), CutaneousB-Cell Lymphoma, Cutaneous Marginal Zone Lymphoma (MZL), Diffuse LargeCell Lymphoma (DLBCL), Diffuse Mixed Small and Large Cell Lymphoma,Diffuse Small Cleaved Cell, Diffuse Small Lymphocytic Lymphoma,Extranodal Marginal Zone B-cell lymphoma, follicular lymphoma,Follicular Small Cleaved Cell (Grade 1), Follicular Mixed Small Cleavedand Large Cell (Grade 2), Follicular Large Cell (Grade 3), IntravascularLarge B-Cell Lymphoma, Intravascular Lymphomatosis, Large CellImmunoblastic Lymphoma, Large Cell Lymphoma (LCL), LymphoblasticLymphoma, MALT Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic largecell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma,chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),extranodal marginal zone B-cell lymphoma-mucosa-associated lymphoidtissue (MALT) lymphoma, Mediastinal Large B-Cell Lymphoma, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma,primary mediastinal B-cell lymphoma, lymphoplasmocytic lymphoma, hairycell leukemia, Waldenstrom's Macroglobulinemia, and primary centralnervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas arecontemplated within the scope of the present invention and apparent tothose of ordinary skill in the art.

DLBCL

Disclosed herein, in certain embodiments, is a method for treating aDLCBL in an individual in need thereof, comprising: administering to theindividual an amount of Compound 1. Further disclosed herein, in certainembodiments, is a method for treating relapsed or refractory DLCBL in anindividual in need thereof, comprising: administering to the individuala therapeutically-effective amount of Compound 1.

As used herein, the term “Diffuse large B-cell lymphoma (DLBCL)” refersto a neoplasm of the germinal center B lymphocytes with a diffuse growthpattern and a high-intermediate proliferation index. DLBCLs representapproximately 30% of all lymphomas and may present with severalmorphological variants including the centroblastic, immunoblastic,T-cell/histiocyte rich, anaplastic and plasmoblastic subtypes. Genetictests have shown that there are different subtypes of DLBCL. Thesesubtypes seem to have different outlooks (prognoses) and responses totreatment. DLBCL can affect any age group but occurs mostly in olderpeople (the average age is mid-60s).

Disclosed herein, in certain embodiments, is a method for treatingdiffuse large B-cell lymphoma, activated B cell-like subtype(ABC-DLBCL), in an individual in need thereof, comprising: administeringto the individual an irreversible Btk inhibitor in an amount from 300mg/day up to, and including, 1000 mg/day. The ABC subtype of diffuselarge B-cell lymphoma (ABC-DLBCL) is thought to arise from post germinalcenter B cells that are arrested during plasmatic differentiation. TheABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% totalDLBCL diagnoses. It is considered the least curable of the DLBCLmolecular subtypes and, as such, patients diagnosed with the ABC-DLBCLtypically display significantly reduced survival rates compared withindividuals with other types of DLCBL. ABC-DLBCL is most commonlyassociated with chromosomal translocations deregulating the germinalcenter master regulator BCL6 and with mutations inactivating the PRDM1gene, which encodes a transcriptional repressor required for plasma celldifferentiation.

A particularly relevant signaling pathway in the pathogenesis ofABC-DLBCL is the one mediated by the nuclear factor (NF)-κBtranscription complex. The NF-κB family comprises 5 members (p50, p52,p65, c-rel and RelB) that form homo- and heterodimers and function astranscriptional factors to mediate a variety of proliferation,apoptosis, inflammatory and immune responses and are critical for normalB-cell development and survival. NF-κB is widely used by eukaryoticcells as a regulator of genes that control cell proliferation and cellsurvival. As such, many different types of human tumors havemisregulated NF-κB: that is, NF-κB is constitutively active. ActiveNF-κB turns on the expression of genes that keep the cell proliferatingand protect the cell from conditions that would otherwise cause it todie via apoptosis.

The dependence of ABC DLBCLs on NF-kB depends on a signaling pathwayupstream of IkB kinase comprised of CARD11, BCL10 and MALT1 (the CBMcomplex). Interference with the CBM pathway extinguishes NF-kB signalingin ABC DLBCL cells and induces apoptosis. The molecular basis forconstitutive activity of the NF-kB pathway is a subject of currentinvestigation but some somatic alterations to the genome of ABC DLBCLsclearly invoke this pathway. For example, somatic mutations of thecoiled-coil domain of CARD11 in DLBCL render this signaling scaffoldprotein able to spontaneously nucleate protein-protein interaction withMALT1 and BCL10, causing IKK activity and NF-kB activation. Constitutiveactivity of the B cell receptor signaling pathway has been implicated inthe activation of NF-kB in ABC DLBCLs with wild type CARD11, and this isassociated with mutations within the cytoplasmic tails of the B cellreceptor subunits CD79A and CD79B. Oncogenic activating mutations in thesignaling adapter MYD88 activate NF-kB and synergize with B cellreceptor signaling in sustaining the survival of ABC DLBCL cells. Inaddition, inactivating mutations in a negative regulator of the NF-kBpathway, A20, occur almost exclusively in ABC DLBCL.

Indeed, genetic alterations affecting multiple components of the NF-κBsignaling pathway have been recently identified in more than 50% ofABC-DLBCL patients, where these lesions promote constitutive NF-κBactivation, thereby contributing to lymphoma growth. These includemutations of CARD11 (˜10% of the cases), a lymphocyte-specificcytoplasmic scaffolding protein that—together with MALT1 and BCL10—formsthe BCR signalosome, which relays signals from antigen receptors to thedownstream mediators of NF-κB activation. An even larger fraction ofcases (˜30%) carry biallelic genetic lesions inactivating the negativeNF-κB regulator A20. Further, high levels of expression of NF-κB targetgenes have been observed in ABC-DLBCL tumor samples. See, e.g., U. Kleinet al., (2008), Nature Reviews Immunology 8:22-23; R. E. Davis et al.,(2001), Journal of Experimental Medicine 194:1861-1874; G. Lentz et al.,(2008), Science 319:1676-1679; M. Compagno et al., (2009), Nature459:712-721; and L. Srinivasan et al., (2009), Cell 139:573-586).

DLBCL cells of the ABC subtype, such as OCI-Ly10, have chronic activeBCR signaling and are very sensitive to the Btk inhibitor describedherein. The irreversible Btk inhibitor described herein potently andirreversibly inhibits the growth of OCI-Ly10 (EC₅₀ continuousexposure=10 nM, EC₅₀ 1 hour pulse=50 nM). In addition, induction ofapoptosis, as shown by capsase activation, Annexin-V flow cytometry andincrease in sub-G0 fraction is observed in OCILy10. Both sensitive andresistant cells express Btk at similar levels, and the active site ofBtk is fully occupied by the inhibitor in both as shown using afluorescently labeled affinity probe. OCI-Ly10 cells are shown to havechronically active BCR signaling to NF-kB which is dose dependentlyinhibited by the Btk inhibitors described herein. The activity of Btkinhibitors in the cell lines studied herein are also characterized bycomparing signal transduction profiles (Btk, PLCγ, ERK, NF-kB, AKT),cytokine secretion profiles and mRNA expression profiles, both with andwithout BCR stimulation, and observed significant differences in theseprofiles that lead to clinical biomarkers that identify the mostsensitive patient populations to Btk inhibitor treatment. See U.S. Pat.No. 7,711,492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp.88-92, the contents of which are incorporated by reference in theirentirety.

Follicular Lymphoma

Disclosed herein, in certain embodiments, is a method for treating afollicular lymphoma in an individual in need thereof, comprising:administering to the individual an amount of Compound 1. Furtherdisclosed herein, in certain embodiments, is a method for treatingrelapsed or refractory follicular lymphoma in an individual in needthereof, comprising: administering to the individual atherapeutically-effective amount of Compound 1.

As used herein, the term “follicular lymphoma” refers to any of severaltypes of non-Hodgkin's lymphoma in which the lymphomatous cells areclustered into nodules or follicles. The term follicular is used becausethe cells tend to grow in a circular, or nodular, pattern in lymphnodes. The average age for people with this lymphoma is about 60.

CLL/SLL

Disclosed herein, in certain embodiments, is a method for treating a CLLor SLL in an individual in need thereof, comprising: administering tothe individual an amount of Compound 1. Further disclosed herein, incertain embodiments, is a method for treating relapsed or refractory CLLor SLL in an individual in need thereof, comprising: administering tothe individual a therapeutically-effective amount of Compound 1.

Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL)are commonly thought as the same disease with slightly differentmanifestations. Where the cancerous cells gather determines whether itis called CLL or SLL. When the cancer cells are primarily found in thelymph nodes, lima bean shaped structures of the lymphatic system (asystem primarily of tiny vessels found in the body), it is called SLL.SLL accounts for about 5% to 10% of all lymphomas. When most of thecancer cells are in the bloodstream and the bone marrow, it is calledCLL.

Both CLL and SLL are slow-growing diseases, although CLL, which is muchmore common, tends to grow slower. CLL and SLL are treated the same way.They are usually not considered curable with standard treatments, butdepending on the stage and growth rate of the disease, most patientslive longer than 10 years. Occasionally over time, these slow-growinglymphomas may transform into a more aggressive type of lymphoma.

Chronic lymphoid leukemia (CLL) is the most common type of leukemia. Itis estimated that 100,760 people in the United States are living with orare in remission from CLL. Most (>75%) people newly diagnosed with CLLare over the age of 50. Currently CLL treatment focuses on controllingthe disease and its symptoms rather than on an outright cure. CLL istreated by chemotherapy, radiation therapy, biological therapy, or bonemarrow transplantation. Symptoms are sometimes treated surgically(splenectomy removal of enlarged spleen) or by radiation therapy(“de-bulking” swollen lymph nodes). Though CLL progresses slowly in mostcases, it is considered generally incurable. Certain CLLs are classifiedas high-risk. As used herein, “high risk CLL” means CLL characterized byat least one of the following 1) 17p13−; 2) 11q22−; 3) unmutated IgVHtogether with ZAP-70+ and/or CD38+; or 4) trisomy 12.

CLL treatment is typically administered when the patient's clinicalsymptoms or blood counts indicate that the disease has progressed to apoint where it may affect the patient's quality of life.

Small lymphocytic leukemia (SLL) is very similar to CLL described supra,and is also a cancer of B-cells. In SLL the abnormal lymphocytes mainlyaffect the lymph nodes. However, in CLL the abnormal cells mainly affectthe blood and the bone marrow. The spleen may be affected in bothconditions. SLL accounts for about 1 in 25 of all cases of non-Hodgkinlymphoma. It can occur at any time from young adulthood to old age, butis rare under the age of 50. SLL is considered an indolent lymphoma.This means that the disease progresses very slowly, and patients tend tolive many years after diagnosis. However, most patients are diagnosedwith advanced disease, and although SLL responds well to a variety ofchemotherapy drugs, it is generally considered to be incurable. Althoughsome cancers tend to occur more often in one gender or the other, casesand deaths due to SLL are evenly split between men and women. Theaverage age at the time of diagnosis is 60 years.

Although SLL is indolent, it is persistently progressive. The usualpattern of this disease is one of high response rates to radiationtherapy and/or chemotherapy, with a period of disease remission. This isfollowed months or years later by an inevitable relapse. Re-treatmentleads to a response again, but again the disease will relapse. Thismeans that although the short-term prognosis of SLL is quite good, overtime, many patients develop fatal complications of recurrent disease.Considering the age of the individuals typically diagnosed with CLL andSLL, there is a need in the art for a simple and effective treatment ofthe disease with minimum side-effects that do not impede on thepatient's quality of life. The instant invention fulfills this longstanding need in the art.

Mantle Cell Lymphoma

Disclosed herein, in certain embodiments, is a method for treating aMantle cell lymphoma in an individual in need thereof, comprising:administering to the individual an amount of Compound 1. Furtherdisclosed herein, in certain embodiments, is a method for treatingrelapsed or refractory Mantle cell lymphoma in an individual in needthereof, comprising: administering to the individual atherapeutically-effective amount of Compound 1.

As used herein, the term, “Mantle cell lymphoma” refers to a subtype ofB-cell lymphoma, due to CD5 positive antigen-naive pregerminal centerB-cell within the mantle zone that surrounds normal germinal centerfollicles. MCL cells generally over-express cyclin D1 due to a t(11:14)chromosomal translocation in the DNA. More specifically, thetranslocation is at t(11;14)(q13;q32). Only about 5% of lymphomas are ofthis type. The cells are small to medium in size. Men are affected mostoften. The average age of patients is in the early 60s. The lymphoma isusually widespread when it is diagnosed, involving lymph nodes, bonemarrow, and, very often, the spleen. Mantle cell lymphoma is not a veryfast growing lymphoma, but is difficult to treat.

Marginal Zone B-cell Lymphoma

Disclosed herein, in certain embodiments, is a method for treating amarginal zone B-cell lymphoma in an individual in need thereof,comprising: administering to the individual an amount of Compound 1.Further disclosed herein, in certain embodiments, is a method fortreating relapsed or refractory marginal zone B-cell lymphoma in anindividual in need thereof, comprising: administering to the individuala therapeutically-effective amount of Compound 1.

As used herein, the term “marginal zone B-cell lymphoma” refers to agroup of related B-cell neoplasms that involve the lymphoid tissues inthe marginal zone, the patchy area outside the follicular mantle zone.Marginal zone lymphomas account for about 5% to 10% of lymphomas. Thecells in these lymphomas look small under the microscope. There are 3main types of marginal zone lymphomas including extranodal marginal zoneB-cell lymphomas, nodal marginal zone B-cell lymphoma, and splenicmarginal zone lymphoma.

MALT

Disclosed herein, in certain embodiments, is a method for treating aMALT in an individual in need thereof, comprising: administering to theindividual an amount of Compound 1. Further disclosed herein, in certainembodiments, is a method for treating relapsed or refractory MALT in anindividual in need thereof, comprising: administering to the individuala therapeutically-effective amount of Compound 1.

The term “mucosa-associated lymphoid tissue (MALT) lymphoma”, as usedherein, refers to extranodal manifestations of marginal-zone lymphomas.Most MALT lymphoma are a low grade, although a minority either manifestinitially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolvefrom the low-grade form. Most of the MALT lymphoma occur in the stomach,and roughly 70% of gastric MALT lymphoma are associated withHelicobacter pylori infection. Several cytogenetic abnormalities havebeen identified, the most common being trisomy 3 or t(11;18). Many ofthese other MALT lymphoma have also been linked to infections withbacteria or viruses. The average age of patients with MALT lymphoma isabout 60.

Nodal Marginal Zone B-Cell Lymphoma

Disclosed herein, in certain embodiments, is a method for treating anodal marginal zone B-cell lymphoma in an individual in need thereof,comprising: administering to the individual an amount of Compound 1.Further disclosed herein, in certain embodiments, is a method fortreating relapsed or refractory nodal marginal zone B-cell lymphoma inan individual in need thereof, comprising: administering to theindividual a therapeutically-effective amount of Compound 1.

The term “nodal marginal zone B-cell lymphoma” refers to an indolentB-cell lymphoma that is found mostly in the lymph nodes. The disease israre and only accounts for 1% of all Non-Hodgkin's Lymphomas (NHL). Itis most commonly diagnosed in older patients, with women moresusceptible than men. The disease is classified as a marginal zonelymphoma because the mutation occurs in the marginal zone of theB-cells. Due to its confinement in the lymph nodes, this disease is alsoclassified as nodal.

Splenic Marginal Zone B-Cell Lymphoma

Disclosed herein, in certain embodiments, is a method for treating asplenic marginal zone B-cell lymphoma in an individual in need thereof,comprising: administering to the individual an amount of Compound 1.Further disclosed herein, in certain embodiments, is a method fortreating relapsed or refractory splenic marginal zone B-cell lymphoma inan individual in need thereof, comprising: administering to theindividual a therapeutically-effective amount of Compound 1.

The term “splenic marginal zone B-cell lymphoma” refers to specificlow-grade small B-cell lymphoma that is incorporated in the World HealthOrganization classification. Characteristic features are splenomegaly,moderate lymphocytosis with villous morphology, intrasinusoidal patternof involvement of various organs, especially bone marrow, and relativeindolent course. Tumor progression with increase of blastic forms andaggressive behavior are observed in a minority of patients. Molecularand cytogenetic studies have shown heterogeneous results probablybecause of the lack of standardized diagnostic criteria.

Burkitt Lymphoma

Disclosed herein, in certain embodiments, is a method for treating aBurkitt lymphoma in an individual in need thereof, comprising:administering to the individual an amount of Compound 1. Furtherdisclosed herein, in certain embodiments, is a method for treatingrelapsed or refractory Burkitt lymphoma in an individual in needthereof, comprising: administering to the individual atherapeutically-effective amount of Compound 1.

The term “Burkitt lymphoma” refers to a type of Non-Hodgkin Lymphoma(NHL) that commonly affects children. It is a highly aggressive type ofB-cell lymphoma that often starts and involves body parts other thanlymph nodes. In spite of its fast-growing nature, Burkitt's lymphoma isoften curable with modern intensive therapies. There are two broad typesof Burkitt's lymphoma—the sporadic and the endemic varieties:

Endemic Burkitt's lymphoma: The disease involves children much more thanadults, and is related to Epstein Barr Virus (EBV) infection in 95%cases. It occurs primarily is equatorial Africa, where about half of allchildhood cancers are Burkitt's lymphoma. It characteristically has ahigh chance of involving the jawbone, a rather distinctive feature thatis rare in sporadic Burkitt's. It also commonly involves the abdomen.

Sporadic Burkitt's lymphoma: The type of Burkitt's lymphoma that affectsthe rest of the world, including Europe and the Americas is the sporadictype. Here too, it's mainly a disease in children. The link betweenEpstein Barr Virus (EBV) is not as strong as with the endemic variety,though direct evidence of EBV infection is present in one out of fivepatients. More than the involvement of lymph nodes, it is the abdomenthat is notably affected in more than 90% of the children. Bone marrowinvolvement is more common than in the sporadic variety.

Waldenstrom Macroglobulinemia

Disclosed herein, in certain embodiments, is a method for treating aWaldenstrom macroglobulinemia in an individual in need thereof,comprising: administering to the individual an amount of Compound 1.Further disclosed herein, in certain embodiments, is a method fortreating relapsed or refractory Waldenstrom macroglobulinemia in anindividual in need thereof, comprising: administering to the individuala therapeutically-effective amount of Compound 1.

The term “Waldenstrom macroglobulinemia”, also known aslymphoplasmacytic lymphoma, is cancer involving a subtype of white bloodcells called lymphocytes. It is characterized by an uncontrolled clonalproliferation of terminally differentiated B lymphocytes. It is alsocharacterized by the lymphoma cells making an antibody calledimmunoglobulin M (IgM). The IgM antibodies circulate in the blood inlarge amounts, and cause the liquid part of the blood to thicken, likesyrup. This can lead to decreased blood flow to many organs, which cancause problems with vision (because of poor circulation in blood vesselsin the back of the eyes) and neurological problems (such as headache,dizziness, and confusion) caused by poor blood flow within the brain.Other symptoms can include feeling tired and weak, and a tendency tobleed easily. The underlying etiology is not fully understood but anumber of risk factors have been identified, including the locus 6p21.3on chromosome 6. There is a 2- to 3-fold risk increase of developing WMin people with a personal history of autoimmune diseases withautoantibodies and particularly elevated risks associated withhepatitis, human immunodeficiency virus, and rickettsiosis.

Multiple Myeloma

Disclosed herein, in certain embodiments, is a method for treating amyeloma in an individual in need thereof, comprising: administering tothe individual an amount of Compound 1. Further disclosed herein, incertain embodiments, is a method for treating relapsed or refractorymyeloma in an individual in need thereof, comprising: administering tothe individual a therapeutically-effective amount of Compound 1.

Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or asKahler's disease (after Otto Kahler) is a cancer of the white bloodcells known as plasma cells. A type of B cell, plasma cells are acrucial part of the immune system responsible for the production ofantibodies in humans and other vertebrates. They are produced in thebone marrow and are transported through the lymphatic system.

Leukemia

Disclosed herein, in certain embodiments, is a method for treating aleukemia in an individual in need thereof, comprising: administering tothe individual an amount of Compound 1. Further disclosed herein, incertain embodiments, is a method for treating relapsed or refractoryleukemia in an individual in need thereof, comprising: administering tothe individual a therapeutically-effective amount of Compound 1.

Leukemia is a cancer of the blood or bone marrow characterized by anabnormal increase of blood cells, usually leukocytes (white bloodcells). Leukemia is a broad term covering a spectrum of diseases. Thefirst division is between its acute and chronic forms: (i) acuteleukemia is characterized by the rapid increase of immature blood cells.This crowding makes the bone marrow unable to produce healthy bloodcells Immediate treatment is required in acute leukemia due to the rapidprogression and accumulation of the malignant cells, which then spillover into the bloodstream and spread to other organs of the body. Acuteforms of leukemia are the most common forms of leukemia in children;(ii) chronic leukemia is distinguished by the excessive build up ofrelatively mature, but still abnormal, white blood cells. Typicallytaking months or years to progress, the cells are produced at a muchhigher rate than normal cells, resulting in many abnormal white bloodcells in the blood. Chronic leukemia mostly occurs in older people, butcan theoretically occur in any age group. Additionally, the diseases aresubdivided according to which kind of blood cell is affected. This splitdivides leukemias into lymphoblastic or lymphocytic leukemias andmyeloid or myelogenous leukemias: (i) lymphoblastic or lymphocyticleukemias, the cancerous change takes place in a type of marrow cellthat normally goes on to form lymphocytes, which are infection-fightingimmune system cells; (ii) myeloid or myelogenous leukemias, thecancerous change takes place in a type of marrow cell that normally goeson to form red blood cells, some other types of white cells, andplatelets.

Within these main categories, there are several subcategories including,but not limited to, Acute lymphoblastic leukemia (ALL), precursor B-cellacute lymphoblastic leukemia (precursor B-ALL; also called precursorB-lymphoblastic leukemia), Acute myelogenous leukemia (AML), Chronicmyelogenous leukemia (CML), and Hairy cell leukemia (HCL). Accordingly,disclosed herein, in certain embodiments, is a method for treating Acutelymphoblastic leukemia (ALL), precursor B-cell acute lymphoblasticleukemia (precursor B-ALL; also called precursor B-lymphoblasticleukemia), Acute myelogenous leukemia (AML), Chronic myelogenousleukemia (CML), or Hairy cell leukemia (HCL) in an individual in needthereof, comprising: administering to the individual an amount ofCompound 1. In some embodiments, the leukemia is a relapsed orrefractory leukemia. In some embodiments, the leukemia is a relapsed orrefractory Acute lymphoblastic leukemia (ALL), relapsed or refractoryprecursor B-cell acute lymphoblastic leukemia (precursor B-ALL; alsocalled precursor B-lymphoblastic leukemia), relapsed or refractory Acutemyelogenous leukemia (AML), relapsed or refractory Chronic myelogenousleukemia (CML), or relapsed or refractory Hairy cell leukemia (HCL).

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are known. See, e.g., Harrison's Principlesof Internal Medicine©,” 16th ed., 2004, The McGraw-Hill Companies, Inc.Dey et al. (2006), Cytojournal 3(24), and the “Revised European AmericanLymphoma” (REAL) classification system (see, e.g., the websitemaintained by the National Cancer Institute).

A number of animal models of are useful for establishing a range oftherapeutically effective doses of irreversible Btk inhibitor compounds,such as Compound 1, for treating any of the foregoing diseases.

The therapeutic efficacy of Compound 1 for any one of the foregoingdiseases can be optimized during a course of treatment. For example, asubject being treated can undergo a diagnostic evaluation to correlatethe relief of disease symptoms or pathologies to inhibition of in vivoBtk activity achieved by administering a given dose of Compound 1.Cellular assays known in the art can be used to determine in vivoactivity of Btk in the presence or absence of an irreversible Btkinhibitor. For example, since activated Btk is phosphorylated attyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specificimmunocytochemical staining of P-Y223 or P-Y551-positive cells can beused to detect or quantify activation of Btk in a population of cells(e.g., by FACS analysis of stained vs unstained cells). See, e.g.,Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus,the amount of the Btk inhibitor compound that is administered to asubject can be increased or decreased as needed so as to maintain alevel of Btk inhibition optimal for treating the subject's diseasestate.

Compound 1 can irreversibly inhibit Btk and may be used to treat mammalssuffering from Bruton's tyrosine kinase-dependent or Bruton's tyrosinekinase mediated conditions or diseases, including, but not limited to,cancer, autoimmune and other inflammatory diseases. Compound 1 has shownefficacy is a wide variety of diseases and conditions that are describedherein.

In some embodiments, Compound 1 is used for the manufacture of amedicament for treating any of the foregoing conditions (e.g.,autoimmune diseases, inflammatory diseases, allergy disorders, B-cellproliferative disorders, or thromboembolic disorders).

Compound 1, and Pharmaceutically Acceptable Salts Thereof

The Btk inhibitor compound described herein (i.e. Compound 1) isselective for Btk and kinases having a cysteine residue in an amino acidsequence position of the tyrosine kinase that is homologous to the aminoacid sequence position of cysteine 481 in Btk. The Btk inhibitorcompound can form a covalent bond with Cys 481 of Btk (e.g., via aMichael reaction).

“Compound 1” or“1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one”or“1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one”or “2-Propen-1-one,1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl-”or ibrutinib or any other suitable name refers to the compound with thefollowing structure:

A wide variety of pharmaceutically acceptable salts is formed fromCompound 1 and includes:

-   -   acid addition salts formed by reacting Compound 1 with an        organic acid, which includes aliphatic mono- and dicarboxylic        acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic        acids, alkanedioic acids, aromatic acids, aliphatic and aromatic        sulfonic acids, amino acids, etc. and include, for example,        acetic acid, trifluoroacetic acid, propionic acid, glycolic        acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,        succinic acid, fumaric acid, tartaric acid, citric acid, benzoic        acid, cinnamic acid, mandelic acid, methanesulfonic acid,        ethanesulfonica acid, p-toluenesulfonic acid, salicylic acid,        and the like;    -   acid addition salts formed by reacting Compound 1 with an        inorganic acid, which includes hydrochloric acid, hydrobromic        acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic        acid, hydrofluoric acid, phosphorous acid, and the like.

The term “pharmaceutically acceptable salts” in reference to Compound 1refers to a salt of Compound 1, which does not cause significantirritation to a mammal to which it is administered and does notsubstantially abrogate the biological activity and properties of thecompound.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms (solvates). Solvatescontain either stoichiometric or non-stoichiometric amounts of asolvent, and are formed during the process of product formation orisolation with pharmaceutically acceptable solvents such as water,ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether(DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methylisobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone,nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane,heptanes, toluene, anisole, acetonitrile, and the like. In one aspect,solvates are formed using, but not limited to, Class 3 solvent(s).Categories of solvents are defined in, for example, the InternationalConference on Harmonization of Technical Requirements for Registrationof Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines forResidual Solvents, Q3C(R3), (November 2005). Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. In some embodiments, solvates of Compound 1, orpharmaceutically acceptable salts thereof, are conveniently prepared orformed during the processes described herein. In some embodiments,solvates of Compound 1 are anhydrous. In some embodiments, Compound 1,or pharmaceutically acceptable salts thereof, exist in unsolvated form.In some embodiments, Compound 1, or pharmaceutically acceptable saltsthereof, exist in unsolvated form and are anhydrous.

In yet other embodiments, Compound 1, or a pharmaceutically acceptablesalt thereof, is prepared in various forms, including but not limitedto, amorphous phase, crystalline forms, milled forms andnano-particulate forms. In some embodiments, Compound 1, or apharmaceutically acceptable salt thereof, is amorphous. In someembodiments, Compound 1, or a pharmaceutically acceptable salt thereof,is amorphous and anhydrous. In some embodiments, Compound 1, or apharmaceutically acceptable salt thereof, is amorphous. In someembodiments, Compound 1, or a pharmaceutically acceptable salt thereof,is amorphous and anhydrous.

In some embodiments, Compound 1 is prepared as outlined in U.S. Pat. No.7,514,444.

Amorphous Compound 1

In some embodiments, Compound 1 is amorphous and anhydrous. In someembodiments, Compound 1 is amorphous. In some embodiments, Compound 1 isamorphous and in spray-dried form.

Preparation of SD Forms

In some embodiments, spray-dried forms of ibrutinib are prepared asoutlined in the Examples. It is noted that solvents, temperatures andother reaction conditions presented herein may vary.

Dosage Forms

The pharmaceutical compositions described herein can be formulated foradministration to a mammal via any conventional means including, but notlimited to, oral, parenteral (e.g., intravenous, subcutaneous, orintramuscular), buccal, intranasal, rectal or transdermal administrationroutes. As used herein, the term “subject” is used to mean an animal,preferably a mammal, including a human or non-human. The terms patientand subject may be used interchangeably.

Moreover, the pharmaceutical compositions described herein, whichinclude Compound 1 can be formulated into any suitable dosage form,including but not limited to, solid oral dosage forms, controlledrelease formulations, fast melt formulations, effervescent formulations,tablets, powders, pills, capsules, delayed release formulations,extended release formulations, pulsatile release formulations,multiparticulate formulations, and mixed immediate release andcontrolled release formulations.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations described herein may be administered as asingle capsule or in multiple capsule dosage form. In some embodiments,the pharmaceutical formulation is administered in two, or three, orfour, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of Compound 1with one or more pharmaceutical excipients to form a bulk blendcomposition. When referring to these bulk blend compositions ashomogeneous, it is meant that the particles of Compound 1 are dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms, such as tablets,pills, and capsules. The individual unit dosages may also include filmcoatings, which disintegrate upon oral ingestion or upon contact withdiluent. These formulations can be manufactured by conventionalpharmacological techniques.

Conventional pharmacological techniques include, e.g., one or acombination of methods: (1) dry mixing, (2) direct compression, (3)milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6)fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Other methods include, e.g., spray drying, pan coating,melt granulation, granulation, fluidized bed spray drying or coating(e.g., wurster coating), tangential coating, top spraying, tableting,extruding and the like.

The pharmaceutical solid dosage forms described herein can includeCompound 1 and one or more pharmaceutically acceptable additives such asa compatible carrier, binder, filling agent, suspending agent, flavoringagent, sweetening agent, disintegrating agent, dispersing agent,surfactant, lubricant, colorant, diluent, solubilizer, moistening agent,plasticizer, stabilizer, penetration enhancer, wetting agent,anti-foaming agent, antioxidant, preservative, or one or morecombination thereof. In still other aspects, using standard coatingprocedures, such as those described in Remington's PharmaceuticalSciences, 20th Edition (2000), a film coating is provided around theformulation of Compound 1. In one embodiment, some or all of theparticles of the Compound 1 are coated. In another embodiment, some orall of the particles of the Compound 1 are microencapsulated. In stillanother embodiment, the particles of the Compound 1 are notmicroencapsulated and are uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the Compound 1 from a solid dosage form matrix asefficiently as possible, disintegrants are often used in theformulation, especially when the dosage forms are compressed withbinder. Disintegrants help rupturing the dosage form matrix by swellingor capillary action when moisture is absorbed into the dosage form.Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® H102, Avicel® PH105, Elcema® P100,Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like. In some embodimentsprovided herein, the disintegrating agent is selected from the groupconsisting of natural starch, a pregelatinized starch, a sodium starch,methylcrystalline cellulose, methylcellulose, croscarmellose,croscarmellose sodium, cross-linked sodium carboxymethylcellulose,cross-linked carboxymethylcellulose, cross-linked croscarmellose,cross-linked starch such as sodium starch glycolate, cross-linkedpolymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodiumalginate, a clay, or a gum. In some embodiments provided herein, thedisintegrating agent is croscarmellose sodium.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA), crospovidone,povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar,such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol,sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gumsuch as acacia, tragacanth, ghatti gum, mucilage of isapol husks,starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL,Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®,polyethylene glycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. Formulators skilled in art can determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like. In someembodiments provided herein, the lubricant is selected from the groupconsisting of stearic acid, calcium hydroxide, talc, corn starch, sodiumstearyl fumerate, stearic acid, sodium stearates, magnesium stearate,zinc stearate, and waxes. In some embodiments provided herein, thelubricant is magnesium stearate.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like. In some embodiments provided herein, the diluent is selectedfrom the group consisting of lactose, sucrose, dextrose, dextrates,maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calciumphosphate, calcium sulfate, starches, modified starches,microcrystalline cellulose, microcellulose, and talc. In someembodiments provided herein, the diluent is microcrystalline cellulose.

The term “non water-soluble diluent” represents compounds typically usedin the formulation of pharmaceuticals, such as calcium phosphate,calcium sulfate, starches, modified starches and microcrystallinecellulose, and microcellulose (e.g., having a density of about 0.45g/cm³, e.g. Avicel, powdered cellulose), and talc.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like. In some embodimentsprovided herein, the surfactant is selected from the group consisting ofsodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitanmonooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate,copolymers of ethylene oxide and propylene oxide. In some embodimentsprovided herein, the surfactant is sodium lauryl sulfate.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in solid dosageforms described herein. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of Compound 1 from the formulation. In other embodiments, thefilm coating aids in patient compliance (e.g., Opadry® coatings or sugarcoating). Film coatings including Opadry® typically range from about 1%to about 3% of the tablet weight. In other embodiments, the compressedtablets include one or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of Compound 1 inside of a capsule. In some embodiments, theformulations (non-aqueous suspensions and solutions) are placed in asoft gelatin capsule. In other embodiments, the formulations are placedin standard gelatin capsules or non-gelatin capsules such as capsulescomprising HPMC. In other embodiments, the formulation is placed in asprinkle capsule, wherein the capsule may be swallowed whole or thecapsule may be opened and the contents sprinkled on food prior toeating. In some embodiments, the therapeutic dose is split into multiple(e.g., two, three, or four) capsules. In some embodiments, the entiredose of the formulation is delivered in a capsule form.

In various embodiments, the particles of Compound 1 and one or moreexcipients are dry blended and compressed into a mass, such as a tablet,having a hardness sufficient to provide a pharmaceutical compositionthat substantially disintegrates within less than about 30 minutes, lessthan about 35 minutes, less than about 40 minutes, less than about 45minutes, less than about 50 minutes, less than about 55 minutes, or lessthan about 60 minutes, after oral administration, thereby releasing theformulation into the gastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with Compound 1 which sufficiently isolate theCompound 1 from other non-compatible excipients. Materials compatiblewith Compound 1 are those that delay the release of the compounds ofCompound 1 in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated Compound 1 may be formulated by methods known by oneof ordinary skill in the art. Such known methods include, e.g., spraydrying processes, spinning disk-solvent processes, hot melt processes,spray chilling methods, fluidized bed, electrostatic deposition,centrifugal extrusion, rotational suspension separation, polymerizationat liquid-gas or solid-gas interface, pressure extrusion, or sprayingsolvent extraction bath. In addition to these, several chemicaltechniques, e.g., complex coacervation, solvent evaporation,polymer-polymer incompatibility, interfacial polymerization in liquidmedia, in situ polymerization, in-liquid drying, and desolvation inliquid media could also be used. Furthermore, other methods such asroller compaction, extrusion/spheronization, coacervation, ornanoparticle coating may also be used.

In one embodiment, the particles of Compound 1 are microencapsulatedprior to being formulated into one of the above forms. In still anotherembodiment, some or most of the particles are coated prior to beingfurther formulated by using standard coating procedures, such as thosedescribed in Remington's Pharmaceutical Sciences, 20th Edition (2000).

In other embodiments, the solid dosage formulations of the Compound 1are plasticized (coated) with one or more layers. Illustratively, aplasticizer is generally a high boiling point solid or liquid. Suitableplasticizers can be added from about 0.01% to about 50% by weight (w/w)of the coating composition. Plasticizers include, but are not limitedto, diethyl phthalate, citrate esters, polyethylene glycol, glycerol,acetylated glycerides, triacetin, polypropylene glycol, polyethyleneglycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol,stearate, and castor oil.

In other embodiments, a powder including the formulations with Compound1 may be formulated to include one or more pharmaceutical excipients andflavors. Such a powder may be prepared, for example, by mixing theformulation and optional pharmaceutical excipients to form a bulk blendcomposition. Additional embodiments also include a suspending agentand/or a wetting agent. This bulk blend is uniformly subdivided intounit dosage packaging or multi-dosage packaging units.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When salts of the compositions describedherein are added to water, the acids and the base react to liberatecarbon dioxide gas, thereby causing “effervescence.” Examples ofeffervescent salts include, e.g., the following ingredients: sodiumbicarbonate or a mixture of sodium bicarbonate and sodium carbonate,citric acid and/or tartaric acid. Any acid-base combination that resultsin the liberation of carbon dioxide can be used in place of thecombination of sodium bicarbonate and citric and tartaric acids, as longas the ingredients were suitable for pharmaceutical use and result in apH of about 6.0 or higher.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the methods and compositions described hereinto achieve delivery to the lower gastrointestinal tract. In someembodiments the polymers described herein are anionic carboxylicpolymers. In other embodiments, the polymers and compatible mixturesthereof, and some of their properties, include, but are not limited to:

Shellac, also called purified lac, a refined product obtained from theresinous secretion of an insect. This coating dissolves in media of pH>7;

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers. TheEudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available assolubilized in organic solvent, aqueous dispersion, or dry powders. TheEudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH >6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP psuedolatex with particles <1 μm. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-55S, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves inpH >5, and it is much less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate, which are well known in the art.Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin(glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,acetylated monoglycerides, glycerol, fatty acid esters, propyleneglycol, and dibutyl phthalate. In particular, anionic carboxylic acrylicpolymers usually will contain 10-25% by weight of a plasticizer,especially dibutyl phthalate, polyethylene glycol, triethyl citrate andtriacetin. Conventional coating techniques such as spray or pan coatingare employed to apply coatings. The coating thickness must be sufficientto ensure that the oral dosage form remains intact until the desiredsite of topical delivery in the intestinal tract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein, which includeCompound 1 are delivered using a pulsatile dosage form. A pulsatiledosage form is capable of providing one or more immediate release pulsesat predetermined time points after a controlled lag time or at specificsites. Many other types of controlled release systems known to those ofordinary skill in the art and are suitable for use with the formulationsdescribed herein. Examples of such delivery systems include, e.g.,polymer-based systems, such as polylactic and polyglycolic acid,plyanhydrides and polycaprolactone; porous matrices, nonpolymer-basedsystems that are lipids, including sterols, such as cholesterol,cholesterol esters and fatty acids, or neutral fats, such as mono-, di-and triglycerides; hydrogel release systems; silastic systems;peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2^(nd)Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,5,977,175, 6,465,014 and 6,932,983, each of which is specificallyincorporated by reference.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of Compound 1 at least one dispersing agent orsuspending agent for oral administration to a subject. The formulationsmay be a powder and/or granules for suspension, and upon admixture withwater, a substantially uniform suspension is obtained.

It is to be appreciated that there is overlap between the above-listedadditives used in the aqueous dispersions or suspensions describedherein, since a given additive is often classified differently bydifferent practitioners in the field, or is commonly used for any ofseveral different functions. Thus, the above-listed additives should betaken as merely exemplary, and not limiting, of the types of additivesthat can be included in formulations described herein. The amounts ofsuch additives can be readily determined by one skilled in the art,according to the particular properties desired.

Dosing and Treatment Regimens

In some embodiments, the amount of Compound 1 that is administered to amammal is from 300 mg/day up to, and including, 1000 mg/day. In someembodiments, the amount of Compound 1 that is administered to a mammalis from 420 mg/day up to, and including, 840 mg/day. In someembodiments, the amount of Compound 1 that is administered to a mammalis about 420 mg/day, about 560 mg/day, or about 840 mg/day. In someembodiments, the amount of Compound 1 that is administered to a mammalis about 420 mg/day. In some embodiments, the amount of Compound 1 thatis administered to a mammal is about 560 mg/day. In some embodiments,the AUC₀₋₂₄ of Compound 1 is between about 150 and about 3500 ng*h/mL.In some embodiments, the AUC₀₋₂₄ of Compound 1 is between about 500 andabout 1100 ng*h/mL. In some embodiments, Compound 1 is administeredorally. In some embodiments, Compound 1 is administered once per day,twice per day, or three times per day. In some embodiments, Compound 1is administered daily. In some embodiments, Compound 1 is administeredonce daily. In some embodiments, Compound 1 is administered every otherday. In some embodiments, the Compound 1 is a maintenance therapy.

Compound 1 can be used in the preparation of medicaments for theinhibition of Btk or a homolog thereof, or for the treatment of diseasesor conditions that would benefit, at least in part, from inhibition ofBtk or a homolog thereof, including a subject diagnosed with ahematological malignancy. In addition, a method for treating any of thediseases or conditions described herein in a subject in need of suchtreatment, involves administration of pharmaceutical compositionscontaining Compound 1, or a pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to said subject.

The compositions containing Compound 1 can be administered forprophylactic, therapeutic, or maintenance treatment. In someembodiments, compositions containing Compound 1 are administered fortherapeutic applications (e.g., administered to a subject diagnosed witha hematological malignancy). In some embodiments, compositionscontaining Compound 1 are administered for therapeutic applications(e.g., administered to a subject susceptible to or otherwise at risk ofdeveloping a hematological malignancy). In some embodiments,compositions containing Compound 1 are administered to a patient who isin remission as a maintenance therapy.

Amounts of Compound 1 will depend on the use (e.g., therapeutic,prophylactic, or maintenance). Amounts of Compound 1 will depend onseverity and course of the disease or condition, previous therapy, thepatient's health status, weight, and response to the drugs, and thejudgment of the treating physician. It is considered well within theskill of the art for one to determine such therapeutically effectiveamounts by routine experimentation (including, but not limited to, adose escalation clinical trial). In some embodiments, the amount ofCompound 1 is from 300 mg/day up to, and including, 1000 mg/day. In someembodiments, the amount of Compound 1 is from 420 mg/day up to, andincluding, 840 mg/day. In some embodiments, the amount of Compound 1 isfrom 400 mg/day up to, and including, 860 mg/day. In some embodiments,the amount of Compound 1 is about 360 mg/day. In some embodiments, theamount of Compound 1 is about 420 mg/day. In some embodiments, theamount of Compound 1 is about 560 mg/day. In some embodiments, theamount of Compound 1 is about 840 mg/day. In some embodiments, theamount of Compound 1 is from 2 mg/kg/day up to, and including, 13mg/kg/day. In some embodiments, the amount of Compound 1 is from 2.5mg/kg/day up to, and including, 8 mg/kg/day. In some embodiments, theamount of Compound 1 is from 2.5 mg/kg/day up to, and including, 6mg/kg/day. In some embodiments, the amount of Compound 1 is from 2.5mg/kg/day up to, and including, 4 mg/kg/day. In some embodiments, theamount of Compound 1 is about 2.5 mg/kg/day. In some embodiments, theamount of Compound 1 is about 8 mg/kg/day.

In some embodiments, pharmaceutical compositions described hereininclude about 140 mg of Compound 1. In some embodiments, a capsuleformulation is prepared that includes about 140 mg of Compound 1. Insome embodiments, 2, 3, 4, or 5 of the capsule formulations areadministered daily. In some embodiments, 3 or 4 of the capsules areadministered daily. In some embodiments, 3 of the 140 mg capsules areadministered once daily. In some embodiments, 4 of the 140 mg capsulesare administered once daily. In some embodiments, the capsules areadministered once daily. In other embodiments, the capsules areadministered multiple times a day.

In some embodiments, Compound 1 is administered daily. In someembodiments, Compound 1 is administered every other day.

In some embodiments, Compound 1 is administered once per day. In someembodiments, Compound 1 is administered twice per day. In someembodiments, Compound 1 is administered three times per day. In someembodiments, Compound 1 is administered four times per day.

In some embodiments, Compound 1 is administered until diseaseprogression, unacceptable toxicity, or individual choice. In someembodiments, Compound 1 is administered daily until disease progression,unacceptable toxicity, or individual choice. In some embodiments,Compound 1 is administered every other day until disease progression,unacceptable toxicity, or individual choice.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, theseverity of the disease, the identity (e.g., weight) of the subject orhost in need of treatment, but can nevertheless be routinely determinedin a manner known in the art according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, and the subject or host beingtreated. In general, however, doses employed for adult human treatmentwill typically be in the range of 0.02-5000 mg per day, or from about1-1500 mg per day. The desired dose may conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative. In some embodiments,each unit dosage form comprises 140 mg of Compound 1. In someembodiments, an individual is administered 1 unit dosage form per day.In some embodiments, an individual is administered 2 unit dosage formsper day. In some embodiments, an individual is administered 3 unitdosage forms per day. In some embodiments, an individual is administered4 unit dosage forms per day.

The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Therapy

In certain instances, it is appropriate to administer Compound 1 incombination with another therapeutic agent.

In one embodiment, the compositions and methods described herein arealso used in conjunction with other therapeutic reagents that areselected for their particular usefulness against the condition that isbeing treated. In general, the compositions described herein and, inembodiments where combinational therapy is employed, other agents do nothave to be administered in the same pharmaceutical composition, and are,because of different physical and chemical characteristics, administeredby different routes. In one embodiment, the initial administration ismade according to established protocols, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration, further modified.

In various embodiments, the compounds are administered concurrently(e.g., simultaneously, essentially simultaneously or within the sametreatment protocol) or sequentially, depending upon the nature of thedisease, the condition of the patient, and the actual choice ofcompounds used. In certain embodiments, the determination of the orderof administration, and the number of repetitions of administration ofeach therapeutic agent during a treatment protocol, is based uponevaluation of the disease being treated and the condition of thepatient.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth.

The individual compounds of such combinations are administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. In one embodiment, the individual compounds will beadministered simultaneously in a combined pharmaceutical formulation.Appropriate doses of known therapeutic agents will be appreciated bythose skilled in the art.

The combinations referred to herein are conveniently presented for usein the form of a pharmaceutical compositions together with apharmaceutically acceptable diluent(s) or carrier(s).

Disclosed herein, in certain embodiments, is a method for treating acancer in an individual in need thereof, comprising: administering tothe individual an amount of Compound 1. In some embodiments, the methodfurther comprises administering a second cancer treatment regimen.

In some embodiments, administering a Btk inhibitor before a secondcancer treatment regimen reduces immune-mediated reactions to the secondcancer treatment regimen. In some embodiments, administering Compound 1before ofatumumab reduces immune-mediated reactions to ofatumumab.

In some embodiments, the second cancer treatment regimen comprises achemotherapeutic agent, a steroid, an immunotherapeutic agent, atargeted therapy, or a combination thereof. In some embodiments, thesecond cancer treatment regimen comprises a B cell receptor pathwayinhibitor. In some embodiments, the B cell receptor pathway inhibitor isa CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor,a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCγ inhibitor, aPKCβ inhibitor, or a combination thereof. In some embodiments, thesecond cancer treatment regimen comprises an antibody, B cell receptorsignaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTORinhibitor, an immunochemotherapy, a radioimmunotherapeutic, a DNAdamaging agent, a proteosome inhibitor, a Cyp3A4 inhibitor, a histonedeacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor,an Hsp90 inhibitor, a telomerase inhibitor, a Jak1/2 inhibitor, aprotease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combinationthereof

In some embodiments, the second cancer treatment regimen compriseschlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide,lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib,paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone,CAL-101, ibritumomab, tositumomab, bortezomib, carfilzomib, pentostatin,endostatin, EPOCH-R, DA-EPOCH-R, rifampin, selinexor, gemcitabine,obinutuzumab, carmustine, cytarabine, melphalan, ublituximab,palbociclib, ACP-196 (Acerta Pharma BV), TGR-1202 (TG Therapeutics,Inc.), TEDDI, TEDD, MEDI4736 (AstraZeneca), ABT-0199 (AbbVie), CC-122(Celgene Corporation), LD-AraC, ketoconazole, etoposide, carboplatin,moxifloxacin, citrovorum, methotrexate, filgrastim, mesna, vincristine,cyclophosphamide, erythromycin, voriconazole, nivolumab or a combinationthereof

In some embodiments, the second cancer treatment regimen comprisescyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, andoptionally, rituximab.

In some embodiments, the second cancer treatment regimen comprisesbendamustine, and rituximab.

In some embodiments, the second cancer treatment regimen comprisesfludarabine, cyclophosphamide, and rituximab.

In some embodiments, the second cancer treatment regimen comprisescyclophosphamide, vincristine, and prednisone, and optionally,rituximab.

In some embodiments, the second cancer treatment regimen comprisesetoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, andoptionally, rituximab.

In some embodiments, the second cancer treatment regimen comprisesdexamethasone and lenalidomide.

In some embodiments, the second cancer treatment comprises a proteasomeinhibitor. In some embodiments, the second treatment comprisesbortezomib. In some embodiments, the second cancer treatment comprisesan epoxyketone. In some embodiments, the second cancer treatmentcomprises epoxomicin. In some embodiments, the second cancer treatmentcomprises a tetrapeptide epoxyketone. In some embodiments, the secondcancer treatment comprises carfilzomib. In some embodiments, the secondcancer treatment comprises disulfram, epigallocatechin-3-gallate,salinosporamide A, ONX 0912, CEP-18770, MLN9708, or MG132.

In some embodiments, the second cancer treatment comprises a Cyp3A4inhibitor. In some embodiments, the second cancer treatment comprisesindinavir, nelfinavir, ritonavir, clarithromycin, itraconazole,ketoconazole, nefazodone. In some embodiments, the second cancertreatment comprises ketoconazole.

In some embodiments, the second cancer treatment comprises a JanusKinase (JAK) inhibitor. In some embodiments, the second treatmentcomprises Lestaurtinib, Tofacitinib, Ruxolitinib, CYT387, Baricitinib orPacritinib.

In some embodiments, the second cancer treatment comprises a histonedeacetylase inhibitor (HDAC inhibitor, HDI). In some embodiments, thesecond cancer treatment comprises a hydroxamic acid (or hydroxamate),such as trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824,and panobinostat (LBH589), a cyclic tetrapeptide, such as trapoxin B, adepsipeptide, a benzamide, such as entinostat (MS-275), CI994, andmocetinostat (MGCD0103), an electrophilic ketone, or an aliphatic acidcompound, such as phenylbutyrate and valproic acid.

In some embodiments, the second cancer treatment comprises a BTKinhibitor. In some embodiments, the Btk inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),GDC-0853 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22,HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (OnoPharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.),PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224(Hanmi Pharmaceutical Company Limited). In some embodiments, the Btkinhibitor is4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide(CGI-1746);7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one(CTA-056);(R)—N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(GDC-0834);6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one(RN-486);N-[5-[5-(4-acetylpiperazine-1-carbonyl)-4-methoxy-2-methylphenyl]sulfanyl-1,3-thiazol-2-yl]-4-[(3,3-dimethylbutan-2-ylamino)methyl]benzamide(BMS-509744, HY-11092); orN-(5-((5-(4-Acetylpiperazine-1-carbonyl)-4-methoxy-2-methylphenyl)thio)thiazol-2-yl)-4-((3-methylbutan-2-yl)amino)methyl)benzamide(HY11066). In some embodiments, the Btk inhibitor is:

Additional cancer treatment regimens include Nitrogen Mustards such asfor example, bendamustine, chlorambucil, chlormethine, cyclophosphamide,ifosfamide, melphalan, prednimustine, trofosfamide; Alkyl Sulfonateslike busulfan, mannosulfan, treosulfan; Ethylene Imines like carboquone,thiotepa, triaziquone; Nitrosoureas like carmustine, fotemustine,lomustine, nimustine, ranimustine, semustine, streptozocin; Epoxidessuch as for example, etoglucid; Other Alkylating Agents such as forexample dacarbazine, mitobronitol, pipobroman, temozolomide; Folic AcidAnalogues such as for example methotrexate, permetrexed, pralatrexate,raltitrexed; Purine Analogs such as for example cladribine, clofarabine,fludarabine, mercaptopurine, nelarabine, tioguanine; Pyrimidine Analogssuch as for example azacitidine, capecitabine, carmofur, cytarabine,decitabine, fluorouracil, gemcitabine, tegafur; Vinca Alkaloids such asfor example vinblastine, vincristine, vindesine, vinflunine,vinorelbine; Podophyllotoxin Derivatives such as for example etoposide,teniposide; Colchicine derivatives such as for example demecolcine;Taxanes such as for example docetaxel, paclitaxel, paclitaxelpoliglumex; Other Plant Alkaloids and Natural Products such as forexample trabectedin; Actinomycines such as for example dactinomycin;Antracyclines such as for example aclarubicin, daunorubicin,doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin,valrubicin, zorubincin; Other Cytotoxic Antibiotics such as for examplebleomycin, ixabepilone, mitomycin, plicamycin; Platinum Compounds suchas for example carboplatin, cisplatin, oxaliplatin, satraplatin;Methylhydrazines such as for example procarbazine; Sensitizers such asfor example aminolevulinic acid, efaproxiral, methyl aminolevulinate,porfimer sodium, temoporfin; Protein Kinase Inhibitors such as forexample dasatinib, erlotinib, everolimus, gefitinib, imatinib,lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus;Other Antineoplastic Agents such as for example alitretinoin,altretamine, amzacrine, anagrelide, arsenic trioxide, asparaginase,bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine,hydroxycarbamide, irinotecan, lonidamine, masoprocol, miltefosein,mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin,romidepsin, sitimagene ceradenovec, tiazofurine, topotecan, tretinoin,vorinostat; Estrogens such as for example diethylstilbenol,ethinylestradiol, fosfestrol, polyestradiol phosphate; Progestogens suchas for example gestonorone, medroxyprogesterone, megestrol; GonadotropinReleasing Hormone Analogs such as for example buserelin, goserelin,leuprorelin, triptorelin; Anti-Estrogens such as for examplefulvestrant, tamoxifen, toremifene; Anti-Androgens such as for examplebicalutamide, flutamide, nilutamide, Enzyme Inhibitors,aminoglutethimide, anastrozole, exemestane, formestane, letrozole,vorozole; Other Hormone Antagonists such as for example abarelix,degarelix; Immunostimulants such as for example histaminedihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex,thymopentin; Immunosuppressants such as for example everolimus,gusperimus, leflunomide, mycophenolic acid, sirolimus; CalcineurinInhibitors such as for example ciclosporin, tacrolimus; OtherImmunosuppressants such as for example azathioprine, lenalidomide,methotrexate, thalidomide; and Radiopharmaceuticals such as for example,iobenguane.

Additional cancer treatment regimens include interferons, interleukins,Tumor Necrosis Factors, Growth Factors, or the like.

Additional cancer treatment regimens include Immunostimulants such asfor example ancestim, filgrastim, lenograstim, molgramostim,pegfilgrastim, sargramostim; Interferons such as for example interferonalfa natural, interferon alfa-2a, interferon alfa-2b, interferonalfacon-1, interferon alfa-n1, interferon beta natural, interferonbeta-1a, interferon beta-1b, interferon gamma, peginterferon alfa-2a,peginterferon alfa-2b; Interleukins such as for example aldesleukin,oprelvekin; Other Immunostimulants such as for example BCG vaccine,glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan,melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, polyI:C, poly ICLC, roquinimex, tasonermin, thymopentin; Immunosuppressantssuch as for example abatacept, abetimus, alefacept, antilymphocyteimmunoglobulin (horse), antithymocyte immunoglobulin (rabbit),eculizumab, efalizumab, everolimus, gusperimus, leflunomide,muromab-CD3, mycophenolic acid, natalizumab, sirolimus; TNF alphaInhibitors such as for example adalimumab, afelimomab, certolizumabpegol, etanercept, golimumab, infliximab; Interleukin Inhibitors such asfor example anakinra, basiliximab, canakinumab, daclizumab, mepolizumab,rilonacept, tocilizumab, ustekinumab; Calcineurin Inhibitors such as forexample ciclosporin, tacrolimus; Other Immunosuppressants such as forexample azathioprine, lenalidomide, methotrexate, thalidomide.

Additional cancer treatment regimens include Adalimumab, Alemtuzumab,Basiliximab, Bevacizumab, Cetuximab, Certolizumab pegol, Daclizumab,Eculizumab, Efalizumab, Gemtuzumab, Ibritumomab tiuxetan, Infliximab,Muromonab-CD3, Natalizumab, Panitumumab, Ranibizumab, Rituximab,Tositumomab, Trastuzumab, or the like, or a combination thereof

Additional cancer treatment regimens include Monoclonal Antibodies suchas for example alemtuzumab, bevacizumab, catumaxomab, cetuximab,edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab,trastuzumab, Immunosuppressants, eculizumab, efalizumab, muromab-CD3,natalizumab; TNF alpha Inhibitors such as for example adalimumab,afelimomab, certolizumab pegol, golimumab, infliximab, InterleukinInhibitors, basiliximab, canakinumab, daclizumab, mepolizumab,tocilizumab, ustekinumab, Radiopharmaceuticals, ibritumomab tiuxetan,tositumomab; Others Monoclonal Antibodies such as for exampleabagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibodyXmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab,arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab,brentuximab vedotin, capromab pendetide, cixutumumab, claudiximab,conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab,epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab,galiximab, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab,inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab,lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibodyCC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab,ramacurimab, ranibizumab, siplizumab, sonepcizumab, tanezumab,tositumomab, trastuzumab, tremelimumab, tucotuzumab celmoleukin,veltuzumab, visilizumab, volociximab, zalutumumab.

Additional cancer treatment regimens include agents that affect thetumor micro-environment such as cellular signaling network (e.g.phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling fromthe B-cell receptor and the IgE receptor). In some embodiments, thesecond agent is a PI3K signaling inhibitor or a syc kinase inhibitor. Inone embodiment, the syk inhibitor is R788. In another embodiment is aPKCγ inhibitor such as by way of example only, enzastaurin.

Examples of agents that affect the tumor micro-environment include PI3Ksignaling inhibitor, syc kinase inhibitor, Protein Kinase Inhibitorssuch as for example dasatinib, erlotinib, everolimus, gefitinib,imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib,temsirolimus; Other Angiogenesis Inhibitors such as for example GT-111,JI-101, R1530; Other Kinase Inhibitors such as for example AC220, AC480,ACE-041, AMG 900, AP24534, Any-614, AT7519, AT9283, AV-951, axitinib,AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398,BGT226, BI 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607,BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036,dinaciclib, dovitinib lactate, E7050, EMD 1214063, ENMD-2076,fostamatinib disodium, GSK2256098, GSK690693, INCB18424, INNO-406,JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265, MK-0457,MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON 01919.Na,OSI-027, OSI-930, Btk inhibitor, PF-00562271, PF-02341066, PF-03814735,PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397,progenipoietin, R547, R763, ramucirumab, regorafenib, R05185426,SAR103168, SCH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901,TKI258, TLN-232, TTP607, XL147, XL228, XL281R05126766, XL418, XL765.

Further examples of anti-cancer agents for use in combination with a Btkinhibitor compound include inhibitors of mitogen-activated proteinkinase signaling, e.g., U0126, PD98059, PD184352, PD0325901,ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002;Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

Other anti-cancer agents that can be employed in combination with a Btkinhibitor compound include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;ifosfamide; iimofosine; interleukin Il (including recombinantinterleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b;interferon alfa-n1; interferon alfa-n3; interferon beta-1 a; interferongamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride.

Other anti-cancer agents that can be employed in combination with a Btkinhibitor compound include: 20-epi-1, 25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-such asfor example growth factor-1 receptor inhibitor; interferon agonists;interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4−;iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Yet other anticancer agents that can be employed in combination with aBtk inhibitor compound include alkylating agents, antimetabolites,natural products, or hormones, e.g., nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,ete.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of alkylating agents that can be employed in combination a Btkinhibitor compound include, but are not limited to, nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan,etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine,thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes(decarbazine, ete.). Examples of antimetabolites include, but are notlimited to folic acid analog (e.g., methotrexate), or pyrimidine analogs(e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin.

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with a Btk inhibitor compound include without limitation thefollowing marketed drugs and drugs in development: Erbulozole (alsoknown as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128),Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829,Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also knownas E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C),Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3,Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7,Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also knownas LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A,Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA),Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothiloneB), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known asBMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone Fand dEpoF), 26-fluoroepothilone), Auristatin PE (also known asNSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia,also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P),LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis),Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also knownas WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academyof Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine(also known as NSC-698666), 3-lAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Where the individual is suffering from or at risk of suffering from anautoimmune disease, an inflammatory disease, or an allergy disease,Compound 1 can be used in with one or more of the following therapeuticagents in any combination: immunosuppressants (e.g., tacrolimus,cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathioprine,mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g.,prednisone, cortisone acetate, prednisolone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, beclometasone,fludrocortisone acetate, deoxycorticosterone acetate, aldosterone),non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoicacids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs,or sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab),abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,or anticholinergics.

Kits/Articles of Manufacture

For use in the therapeutic methods of use described herein, kits andarticles of manufacture are also described herein. Such kits include acarrier, package, or container that is compartmentalized to receive oneor more containers such as vials, tubes, and the like, each of thecontainer(s) comprising one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. In one embodiment, thecontainers are formed from a variety of materials such as glass orplastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical productsinclude, e.g., U.S. Pat. No. 5,323,907. Examples of pharmaceuticalpackaging materials include, but are not limited to, blister packs,bottles, tubes, bags, containers, bottles, and any packaging materialsuitable for a selected formulation and intended mode of administrationand treatment.

In some embodiments, the compounds or compositions described herein, arepresented in a package or dispenser device which may contain one or moreunit dosage forms containing the active ingredient. The compound orcomposition described herein is packaged alone, or packaged with anothercompound or another ingredient or additive. In some embodiments, thepackage contains one or more containers filled with one or more of theingredients of the pharmaceutical compositions. In some embodiments, thepackage comprises metal or plastic foil, such as a blister pack. In someembodiments, the package or dispenser device is accompanied byinstructions for administration, such as instructions for administeringthe compounds or compositions for treating a neoplastic disease. In someembodiments, the package or dispenser is accompanied with a noticeassociated with the container in form prescribed by a governmentalagency regulating the manufacture, use, or sale of pharmaceuticals,which notice is reflective of approval by the agency of the form of thedrug for human or veterinary administration. In some embodiments, suchnotice, for example, is the labeling approved by the U.S. Food and DrugAdministration for prescription drugs, or the approved product insert.In some embodiments, compositions include a compound described hereinformulated in a compatible pharmaceutical carrier are prepared, placedin an appropriate container, and labeled for treatment of an indicatedcondition.

For example, the container(s) include Compound 1, optionally in acomposition or in combination with another agent as disclosed herein.Such kits optionally include an identifying description or label orinstructions relating to its use in the methods described herein.

A kit typically includes labels listing contents and/or instructions foruse, and package inserts with instructions for use. A set ofinstructions will also typically be included.

In one embodiment, a label is on or associated with the container. Inone embodiment, a label is on a container when letters, numbers or othercharacters forming the label are attached, molded or etched into thecontainer itself; a label is associated with a container when it ispresent within a receptacle or carrier that also holds the container,e.g., as a package insert. In one embodiment, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. The label also indicates directions for use of thecontents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions are presented ina pack or dispenser device which contains one or more unit dosage formscontaining a compound provided herein. The pack, for example, containsmetal or plastic foil, such as a blister pack. In one embodiment, thepack or dispenser device is accompanied by instructions foradministration. In one embodiment, the pack or dispenser is alsoaccompanied with a notice associated with the container in formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the drug for human or veterinary administration.Such notice, for example, is the labeling approved by the U.S. Food andDrug Administration for prescription drugs, or the approved productinsert. In one embodiment, compositions containing a compound providedherein formulated in a compatible pharmaceutical carrier are alsoprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition.

EXAMPLES

The following ingredients, formulations, processes and procedures forpracticing the methods disclosed herein correspond to that describedabove.

Example 1 Preparation of Spray-dried Forms of1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(ibrutinib) (Compound 1)

The spray dry mixture solvent was prepared by solubilizing bothibrutinib and a polymer in acetone at a total solid weight concentrationof 10%. The mixture was thoroughly mixed until completely dissolved toavoid solid clumps during spraying. Acetone was selected as solvent forspray drying because it provided adequate ibrutinib and polymersolubility and was more favorable solvent than other solventsconsidered. Ibrutinib solid weight of 2% or 5% with 8% or 5% polymersolvent mixtures were spray dried at 15 ml/min speed with a nozzle sizeof 1.5 mm and nozzle pressure at 20 psi. The inlet temperature was setbetween 70 to 80° C., and the outlet temperature was set between 40 to45° C. The drying gas flow was maintained at 35 m³/hr. Secondary dryingwas performed at 40° C. in an oven for about 16 hours to further reducemoisture or acetone from the solid dispersed powder. Spray drying runsyielded from 80 to 90% with no material significant accumulation on thespray dry chamber across a wide range of spray-drying conditions and/ordifferent solvent mixtures during screening phase.

TABLE 1 Examples of Spray Dried (SD) Compositions Comprising IbrutinibSD Composition Components Ratio b Ibrutinib:Soluplus ® 1:1 cIbrutinib:HPMCAS-M 1:1 d Ibrutinib:HPMCAS-M 1:4 e Ibrutinib:PVP-VA 1:2 fIbrutinib:PVP-VA:soluplus   1:1:1 g Ibrutinib:PVP-VA 1:1

Example 2 Chiral Purity Determination

Chiral purity of Compound 1 was determined by using a Lux Cellulose-1chiral column by normal phase HPLC. The mobile phase is composed of 20%isopropyl alcohol and 80% hexanes. The enantiomers of1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-oneare detected at 260 nm. In one embodiment, Compound 1 is dissolved in amixture of Hexanes: IPA=(7:3) to obtain a concentration of approximately0.2 mg/mL and the chiral purity of the sample is analyzed. The contentof the R enantiomer is determined by peak area normalization of theenantiomer peaks and is expressed in weight to weight percent. In someembodiments, a sample of Compound 1 includes less than 5.0%, less than4.0%, less than 3.0%, less than 2.0%, or less than 1.0%, of the(S)-isomer. In some embodiments, a sample of Compound 1 includes lessthan 1.0% of the (S)-isomer.

Example 3 Formulation A (Capsule)

In one embodiment, capsule formulations of Compound 1 for administrationto humans are prepared with the following ingredients:

TABLE 2 Formulation A Excipient or Active % (w/w) API Ibrutinib 42.42Diluent Microcrystalline cellulose 45.88 Surfactant Sodium LaurylSulfate 4.25 Disintegrant Croscarmellose sodium 6.97 Lubricant MagnesiumStearate 0.48 Capsule Gelatin —

In some embodiments, the manufacturing process includes the followingsteps: i) weigh the indicated amount of the components, ii) mixtogether, iii) granulate the mixture, (iii) prepare final blend byadding additional disintegrant, surfactant and lubricant (iv) fill thefinal blend into an appropriate size capsule, (v) close the capsule. Insome embodiments, the capsules are stored at room temperature for anextended period of time until they are used.

Example 4 Formulation B (SD with Soluplus®)

Ibrutinib with Soluplus solid dispersion intermediate (50% activespray-dried ibrutinib) was blended with lactose, microcrystallinecellulose, croscarmellose, silicon dioxide and 0.25% of magnesium statein a V-blender for 10 minutes. The blend mixture was then screenedthrough a size 20 mesh. Additional magnesium stearate of 0.25% was addedto the post-screened blend and blended additionally for 3 minutes. Thefinal blend was roller compacted to obtain a ribbon or slug using aroller compactor or a single press station. Compacted ribbons or slugswere milled using a mill granulator and screened through a size 20 meshbefore compressing into tablets using a single station tablet press.

TABLE 3 Formulation B Excipient % (w/w) Spray Dried API* Ibrutinib 25.00Spray Dried Soluplus ® 25.00 Polymer* Diluent 1 Lactose 17.00 Diluent 2Microcrystalline cellulose 25.50 Disintegrant Croscarmellose sodium 6.00Glidant Colloidal Silicon Dioxide 1.00 Lubricant Magnesium Stearate 0.50*50% active spray-dried ibrutinib

Example 5 Formulation C (SD with HPMCAS-M)

Ibrutinib with HPMCAS-M solid dispersion intermediate (50% activespray-dried ibrutinib) was blended with lactose, microcrystallinecellulose, croscarmellose, silicon dioxide and 0.25% of magnesium statein a V-blender for 10 minutes. The blend mixture was then screenedthrough a size 20 mesh. Additional magnesium stearate of 0.25% was addedto the post-screened blend and blended additionally for 3 minutes. Thefinal blend was roller compacted to obtain a ribbon or slug using aroller compactor or a single press station. Compacted ribbons or slugswere milled using a mill granulator and screened through a size 20 meshbefore compressing into tablets using a single station tablet press.

TABLE 4 Formulation C Excipient % (w/w) Spray Dried API* Ibrutinib26.925 Spray Dried HPMCAS-M 26.925 Polymer* Diluent 1 Lactose 14.00Diluent 2 Microcrystalline cellulose 24.65 Disintegrant Croscarmellosesodium 6.00 Glidant Colloidal Silicon Dioxide 1.00 Lubricant MagnesiumStearate 0.50 *50% active spray-dried ibrutinib

Example 6 Formulation D (SD with HPMCAS-M)

Ibrutinib with HPMCAS-M solid dispersion intermediate (20% activespray-dried ibrutinib) was blended with lactose, microcrystallinecellulose, croscarmellose, silicon dioxide and 0.25% of magnesium statein a V-blender for 10 minutes. The blend mixture was then screenedthrough a size 20 mesh. Additional magnesium stearate of 0.25% was addedto the post-screened blend and blended additionally for 3 minutes. Thefinal blend was roller compacted to obtain a ribbon or slug using aroller compactor or a single press station. Compacted ribbons or slugswere milled using a mill granulator and screened through a size 20 meshbefore compressing into tablets using a single station tablet press.

TABLE 5 Formulation D Excipient % (w/w) Spray Dried API* Ibrutinib 10.77Spray Dried HPMCAS-M 43.08 Polymer* Diluent 1 Lactose 14.00 Diluent 2Microcrystalline cellulose 24.65 Disintegrant Croscarmellose sodium 6.00Glidant Colloidal Silicon Dioxide 1.00 Lubricant Magnesium Stearate 0.50*20% active spray-dried ibrutinib

Example 6 Tablet Formulations E, F and G (SD withPolyvinylpyrrolidone/Vinyl Acetate (PVP-VA) Co-polymer and OptionalSoluplus)

TABLE 6 Tablet Formulations E and F (mg) Component % w/w Formulation EFormulation F Spray Dried Ibrutinib 46.67 140 140 Composition PVP-VA 280140 soluplus 0 140 Prosolv ® EasyTab* 22.83 205.47 205.47 Sodium StearylFumarate 0.25 2.25 2.25 Intragranular Total 69.75 627.72 627.72Crospovidone/Kollidon CL F 30.00 270.00 270.00 Sodium Stearyl Fumarate0.25 2.25 2.25 Extragranular Total 30.25 272.25 272.25 Total 100.00899.97 899.97 *Prosolv ® EasyTab (JRS PHARMA LP, USA) is an excipientcomposite comprising a binder-filler, glidant, disintegrant, andlubricant, in particular, microcrystalline cellulose, colloidal silicondioxide, sodium starch glycolate, and sodium stearyl fumarate.

TABLE 7 Tablet Formulation G Component % w/w mg Spray Dried Ibrutinib31.11 140 Composition PVP-VA 140 Prosolv ® EasyTab 22.83 205.47 SodiumStearyl Fumarate 0.25 2.25 Intragranular Total 54.19 487.72Extra-Granular Polymer 15.56 140 Soluplus Crospovidone/Kollidon CL F30.00 270.00 Sodium Stearyl Fumarate 0.25 2.25 Extragranular Total 45.81412.25 Total 100.00 899.97

Example 7 Immediate Release Tablets

In some embodiments, tablets are prepared with the components set forthin Table 8.

TABLE 8 Components of Tablet Formulation Ingredient Range Spray-driedibrutinib 5% to 50% Hypromellose 2% to 10% Croscarmellose sodium 0% to15% Microcrystalline cellulose 5% to 50% Lactose 10% to 75%  Magnesiumstearate 0.25% to 2.5%  Total Tablet weight range: 300 mg to 1000 mg

Example 8 Immediate Release Tablets

In some embodiments, tablets are prepared with the components set forthin Table 9.

TABLE 9 Components of Tablet Formulation Tested Propose Component TestedExcipient % w/w Range % w/w Spray Dried Ibrutinib 10 to 25 1 to 65 APISpray Dried HPMCAS & Soluplus 25 to 40 4 to 65 Polymer Diluent 1 Lactose14 to 17 0 to 80 Diluent 2 Microcrystalline cellulose 25  0 to 80Disintegrant Croscarmellose sodium 6 3 to 10 Glidant Colloidal SiliconDioxide 1 0 to 2  Lubricant Magnesium Stearate 0.25 to 0.5  0 to 1 

Manufacturing process will typically be granulation (dry, wet or melt)or direct compression.

Example 9 PK Study of Compound 1 in Different Formulations

In vivo experiments were conducted to evaluate the potential benefit ofthe solid dispersion formulations relative to conventional formulationssuch as capsule formulation.

Particularly, the pharmacokinetics of ibrutinib in capsule (FormulationA) versus different solid dispersion formulations (Formulations B, C,and D) was studied in fasted male beagle dogs following single oraladministration of 140 mg ibrutinib formulations administered in a Latinsquare crossover design. FIG. 1 shows mean plasma concentration-timeprofiles of ibrutinib following single oral dose administration ofdifferent ibrutinib formulations to fasted beagle dogs (Dose=140 mg). Ingeneral, all the solid dispersion formulations tested showed higherconcentrations than the capsule formulation A. Specifically, soliddispersion formulations C and D showed on average 9- to 10-fold higherexposure than seen with the capsule formulation (Table 10).

Furthermore, the solid dispersion formulations of ibrutinib withHPMCAS-M (Formulations C and D) showed about 16-18 fold increase inC_(max), and about 9-10 fold increase in AUC. Pharmacokinetics of soliddispersion formulations E, F and G were evaluated in pentagastrintreated fasted male beagle dogs following single oral administration of140 mg ibrutinib in comparison to capsule (Formulation A). Pretreatmentwith pentagastrin decreases dog gastric pH to (1-3) similar to humangastric pH and can be used to predict performance in humans. Inpentagastrin pretreated dogs, solid dispersion formulations (E, F and G)showed approximately 2- to 3-fold increase in exposure (FIG. 2) andsignificantly reduced variability in exposure (Table 10).

Additionally, reduced variability in ibrutinib exposure (both C_(max)and AUC) was consistently observed with solid dispersion formulationsC-G when compared to capsule formulation (Table 10).

TABLE 10 Mean (% CV) Ibrutinib Plasma PK Parameters Following SingleDose Administration of Different Ibrutinib Formulations to Fasted BeagleDogs (n = 7) Formu- C_(max**) T_(max) T_(1/2) AUC lation (ng/mL) (h) (h)(ng * h/mL) F_(rel) (%) A 49.7 (77.0) 2.14 3.92 (92.9) 216 (87.0) N/A(Cap- sule) B 128 (202) 5.00 1.49 (ND) 378 (155) 235 (164) C  551 (56.0)1.00 2.52 (95.1) 1321 (45.0)   875 (65.0) D  799 (67.0) 2.00 2.70 (54.3)1674 (55.0)  1014 (60.0)  E 783 (39)  0.929 3.21 1394 (49)  227 F 636(32)  1.00 4.52 1340 (49)  235 G 784 (33)  0.929 2.44 1488 (41)  261F_(rel): (AUC_(Formulation B,C or D)/AUC_(Formulation A)) * 100**coefficient of variation (CV) values are given in parenthesis N/A: notapplicable; ND: not determined

In summary, the solid dispersion formulations of ibrutinib comprisingthe spray-dried form of ibrutinib proved to be advantageous over thecapsule formulations.

Example 10 Drug Dissolution

In-vitro dissolution test for ibrutinib solid dispersion tablets orcapsules were performed with 900 ml of 0.05M phosphate buffer at pH 6.8with 3% (w/v) polysorbate 20 using USP <711> apparatus 2. The paddlespeed was at 75 rpm from 0 to 60 minutes and increased to 250 rpm from60 to 75 minutes. Samples are filtered at time of collection andanalyzed using isocratic reversed-phase high performance liquidchromatography (HPLC) with ultraviolet (UV) detection per Pharmacyclicsmethod.

FIG. 3 shows the improved dissolution of the solid dispersion tablet(Formulations C and D) over the dissolution of the capsule formulation(Formulation A). FIG. 4 Illustrates the dissolution of the soliddispersion tablet Formulations E, F and G as compared to the capsuleformulation (Formulation A).

Example 11 Safety and Tolerability Study of Compound 1 in ChronicLymphocytic Leukemia

Purpose: The purpose of this study is to establish the safety andoptimal dose of orally administered Compound 1 (420 mg/day) in patientswith B-cell chronic lymphocytic leukemia/small lymphocyticlymphoma/diffuse well-differentiated lymphocytic lymphoma.

Primary Outcome Measures: Safety and tolerability of Compound 1(frequency, severity, and relatedness of adverse events).

Secondary Outcome Measures: Pharmacokinetic/Pharmacodynamic assessments.Tumor response—overall response rate as defined by recent guidelines onCLL and SLL (B cell lymphoma) and duration of response.

Eligibility: 18 Years and older; both genders are eligible.

Inclusion Criteria: 1. For treatment-naive group only: Men and women ≧65years of age with confirmed diagnosis of CLL/SLL, who require treatmentper NCI or International Working Group guidelines 11-14. 2. Forrelapsed/refractory group only: Men and women ≧18 years of age with aconfirmed diagnosis of relapsed/refractory CLL/SLL unresponsive totherapy (ie, failed ≧2 previous treatments for CLL/SLL and at least 1regimen had to have had a purine analog [eg, fludarabine] for subjectswith CLL). 3. Body weight ≧40 kg. 4. ECOG performance status of ≦2. 5.Agreement to use contraception during the study and for 30 days afterthe last dose of study drug if sexually active and able to bearchildren. 6. Willing and able to participate in all required evaluationsand procedures in this study protocol including swallowing capsuleswithout difficulty. 7. Ability to understand the purpose and risks ofthe study and provide signed and dated informed consent andauthorization to use protected health information (in accordance withnational and local subject privacy regulations).

Exclusion Criteria: 1. A life-threatening illness, medical condition ororgan system dysfunction which, in the investigator's opinion, couldcompromise the subject's safety, interfere with the absorption ormetabolism of Compound 1 PO, or put the study outcomes at undue risk. 2.Any immunotherapy, chemotherapy, radiotherapy, or experimental therapywithin 4 weeks before first dose of study drug (corticosteroids fordisease-related symptoms allowed but require 1-week washout before studydrug administration). 3. Central nervous system (CNS) involvement bylymphoma. 4. Major surgery within 4 weeks before first dose of studydrug. 5. Creatinine >1.5× institutional upper limit of normal (ULN);total bilirubin >1.5×ULN (unless due to Gilbert's disease); andaspartate aminotransferase (AST) or alanine aminotransferase(ALT) >2.5×ULN unless disease related. 6. Concomitant use of medicinesknown to cause QT prolongation or torsades de pointes. 7. Significantscreening electrocardiogram (ECG) abnormalities including left bundlebranch block, 2nd degree AV block type II, 3rd degree block,bradycardia, and QTc >470 msec. 8. Lactating or pregnant.

Example 12 Safety and Efficacy of Compound 1 in Subjects withRelapsed/Refractory Mantle Cell Lymphoma (MCL)

The primary objective of this trial is to evaluate the efficacy ofCompound 1 in relapsed/refractory subjects with Mantle Cell Lymphoma(MCL). The secondary objective is to evaluate the safety of a fixeddaily dosing regimen of Compound 1 (560 mg/day in the form of capsules)in this population.

Primary Outcome Measures: To measure the number of participants with aresponse to Compound 1.

Secondary Outcome Measures: To measure the number of participants withadverse events as a measure of safety and tolerability. To measurepharmacokinetics to assist in determining how the body responds to thestudy drug. Patient reported outcomes (to measure the number ofparticipants reported outcomes in determining the health related qualityof life).

Eligibility: 18 Years and older; both genders are eligible.

Inclusion Criteria: Men and women ≧18 years of age. ECOG performancestatus of ≦2. Pathologically confirmed MCL, with documentation of eitheroverexpression of cyclin D1 or t(11;14), and measurable disease on crosssectional imaging that is ≧2 cm in the longest diameter and measurablein 2 perpendicular dimensions. Documented failure to achieve at leastpartial response (PR) with, or documented disease progression diseaseafter, the most recent treatment regimen. At least 1, but no more than5, prior treatment regimens for MCL (Note: Subjects having received ≧2cycles of prior treatment with bortezomib, either as a single agent oras part of a combination therapy regimen, will be considered to bebortezomib-exposed.). Willing and able to participate in all requiredevaluations and procedures in this study protocol including swallowingcapsules without difficulty. Ability to understand the purpose and risksof the study and provide signed and dated informed consent andauthorization to use protected health information (in accordance withnational and local subject privacy regulations).

Major exclusion criteria: Prior chemotherapy within 3 weeks,nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4weeks, radio- or toxin-immunoconjugates within 10 weeks, radiationtherapy within 3 weeks, or major surgery within 2 weeks of first dose ofstudy drug. Any life-threatening illness, medical condition or organsystem dysfunction which, in the investigator's opinion, couldcompromise the subject's safety, interfere with the absorption ormetabolism of Compound 1 capsules, or put the study outcomes at unduerisk. Clinically significant cardiovascular disease such as uncontrolledor symptomatic arrhythmias, congestive heart failure, or myocardialinfarction within 6 months of screening, or any Class 3 or 4 cardiacdisease as defined by the New York Heart Association FunctionalClassification. Malabsorption syndrome, disease significantly affectinggastrointestinal function, or resection of the stomach or small bowel orulcerative colitis, symptomatic inflammatory bowel disease, or partialor complete bowel obstruction. Any of the following laboratoryabnormalities: 1. Absolute neutrophil count (ANC)<750 cells/mm3(0.75×109/L) unless there is documented bone marrow involvement. 2.Platelet count <50,000 cells/mm3 (50×109/L) independent of transfusionsupport unless there is documented bone marrow involvement. 3. Serumaspartate transaminase (AST/SGOT) or alanine transaminase(ALT/SGPT) >3.0× upper limit of normal (ULN). 4. Creatinine >2.0×ULN.

Example 13 Phase 2 Study of the Combination of Compound 1 and Rituximabin High-Risk Chronic Lymphocytic Leukemia and Small Lymphocytic LymphomaPatients

Purpose: The goal of this clinical research study is to learn ifCompound 1 combined with rituximab can help to control chroniclymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Thesafety of this combination will also be studied.

Rituximab (375 mg/m²) given intravenously (IV) on Day 1, Day 8, Day 15,and Day 22, then continued once every 4 weeks only on Days 1 duringcycles 2-6. Compound 1 started on Day 2 of cycle 1 at a dose of 420 mg(3×140-mg capsules) orally daily and will be continued daily.

Primary Outcome Measures: Progression free survival (PFS) [Time Frame: 3months]—progression free survival defined as the time interval fromtreatment to progressive disease or death, whichever happens earlier.Patients in complete remission (CR), partial remission (PR) or stabledisease (SD) are all counted as progression-free. Survival or times toprogression functions estimated using the Kaplan-Meier method.

Secondary Outcome Measures: Toxicity [Time Frame: 3 months]—toxicityreported by type, frequency and severity. Worst toxicity grades perpatient tabulated for selected adverse events and laboratorymeasurements. Toxicity (grade 3 or 4) monitored based on the Bayesianmodel (beta-binomial) by assuming a priori probability of toxicityfollowing beta(1,1).

Eligibility: 18 Years and older; both genders are eligible.

Inclusion Criteria: 1. Patients must have a diagnosis of high-riskCLL/SLL and be previously treated with up to 3 lines of prior therapy.High-risk CLL and high-risk SLL is defined by the presence of a 17pdeletion or 11q deletion or TP53 mutation. Any CLL and SLL patient whohas a short remission duration of less than 3 years after priorfirst-line chemo-immunotherapy, such as the FCR regimen, also fulfillscriteria of high-risk CLL/SLL, regardless of the presence or absence ofcytogenetic abnormalities. 2. CLL and SLL patients with 17p deletion orTP53 mutation will not be required to have received any prior therapy,given the poor outcome of CLL/SLL patients to standard frontlinechemo-immunotherapy, such patients will be eligible if they areuntreated or if they have received up to 3 lines of prior therapy. 3.Patients must have an indication for treatment by 2008 IWCLL Criteria.4. Patients age >18 years at the time of signing informed consent.Understand and voluntarily sign an informed consent. Be able to complywith study procedures and follow-up examinations. 5. ECOG/WHOperformance status of 0-1. 6. Patients of childbearing potential must bewilling to practice highly effective birth control (e.g., condoms,implants, injectables, combined oral contraceptives, some intrauterinedevices [IUDs], sexual abstinence, or sterilized partner) during thestudy and for 30 days after the last dose of study drug. Women ofchildbearing potential include any female who has experienced menarcheand who has not undergone successful surgical sterilization(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) oris not postmenopausal. Post menopause is defined as follows:Amenorrhea >/=12 consecutive months without another cause and adocumented serum follicle stimulating hormone (FSH) level >35 mIU/mL; amale of childbearing potential is any male that has not been surgicallysterilized. 7. Adequate renal and hepatic function as indicated by allof the following: Total bilirubin <1=1.5× institutional Upper Limit ofNormal (ULN) except for patients with bilirubin elevation due toGilbert's disease who will be allowed to participate; an ALT <1=2.5×ULN;and an estimated creatinine clearance (CrCl) of >30 mL/min, ascalculated by the Cockroft-Gault equation unless disease related. 8.Free of prior malignancies for 3 years with exception of currentlytreated basal cell, squamous cell carcinoma of the skin, or carcinoma insitu of the cervix or breast. 9. A urine pregnancy test (within 7 daysof Day 1) is required for women with childbearing potential

Exclusion Criteria: 1. Pregnant or breast-feeding females. 2. Treatmentincluding chemotherapy, chemo-immunotherapy, monoclonal antibodytherapy, radiotherapy, high-dose corticosteroid therapy (more than 60 mgPrednisone or equivalent daily), or immunotherapy within 21 days priorto enrollment or concurrent with this trial. 3. Investigational agentreceived within 30 days prior to the first dose of study drug or havepreviously taken Compound 1. If received any investigational agent priorto this time point, drug-related toxicities must have recovered to Grade1 or less prior to first dose of study drug. 4. Systemic fungal,bacterial, viral, or other infection not controlled (defined asexhibiting ongoing signs/symptoms related to the infection and withoutimprovement, despite appropriate antibiotics or other treatment). 5.Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) orautoimmune thrombocytopenia (ITP). 6. Patients with severe hematopoieticinsufficiency, as defined by an absolute neutrophil count of less than500/micro-L and/or a platelet count of less than 30,000/micro-L at timeof screening for this protocol. 7. Any other severe concurrent disease,or have a history of serious organ dysfunction or disease involving theheart, kidney, liver or other organ system that may place the patient atundue risk to undergo therapy with Compound 1 and rituximab. 8.Significant cardiovascular disease such as uncontrolled or symptomaticarrhythmias, congestive heart failure, or myocardial infarction within 6months of screening, or any Class 3 or 4 cardiac disease as defined bythe New York Heart Association Functional Classification. 9. Significantscreening ECG abnormalities including left bundle branch block, 2nddegree AV block type II, 3rd degree block, bradycardia, and QTc >470msec. 10. Any serious medical condition, laboratory abnormality, orpsychiatric illness that places the subject at unacceptable risk ifhe/she were to participate in the study. 11. History of stroke orcerebral hemorrhage within 6 months. 12. Evidence of bleeding diathesisor coagulopathy. 13. Major surgical procedure, open biopsy, orsignificant traumatic injury within 28 days prior to Day 1, anticipationof need for major surgical procedure during the course of the study. 14.Minor surgical procedures, fine needle aspirations or core biopsieswithin 7 days prior to Day 1. Bone marrow aspiration and/or biopsy areallowed. 15. Serious, non-healing wound, ulcer, or bone fracture. 16.Treatment with Coumadin. Patients who recently received Coumadin must beoff Coumadin for at least 7 days prior to start of the study. 17. Anychemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, orfludarabine), immunotherapy (e.g., alemtuzumab, or ofatumumab), bonemarrow transplant, experimental therapy, or radiotherapy is prohibitedduring therapy on this study. 18. Use of medications known to prolongQTc interval or that may be associated with Torsades de Pointes (referto Appendix F) are prohibited within 7 days of starting study drug andduring study-drug treatment.

The examples and embodiments described herein are illustrative andvarious modifications or changes suggested to persons skilled in the artare to be included within this disclosure. As will be appreciated bythose skilled in the art, the specific components listed in the aboveexamples may be replaced with other functionally equivalent components,e.g., diluents, binders, lubricants, fillers, and the like.

What is claimed is:
 1. A solid dispersion formulation, wherein theformulation comprises a) about 49 to about 51% w/w of 50% activespray-dried ibrutinib, wherein ibrutinib is a compound of formula (I),

b) about 16 to about 18% w/w of lactose, c) about 24 to about 26% w/w ofmicrocrystalline cellulose, d) about 5 to about 7% w/w of croscarmellosesodium, e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, andf) about 0.2 to about 0.8% w/w of magnesium stearate; and wherein the50% active spray-dried ibrutinib is a spray-dried ibrutinib compositioncomprising about 50% w/w of ibrutinib dispersed into a polymer matrix;and the polymer in the polymer matrix is hydroxypropyl methyl celluloseacetate succinate (HPMCAS).
 2. A solid dispersion formulation, whereinthe formulation comprises a) about 52 to about 54% w/w of 20% activespray-dried ibrutinib, wherein ibrutinib is a compound of formula (I),

b) about 13 to about 15% w/w of lactose, c) about 24 to about 26% w/w ofmicrocrystalline cellulose, d) about 5 to about 7% w/w of croscarmellosesodium, e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, andf) about 0.4 to about 0.6% w/w of magnesium stearate; and wherein the20% active spray-dried ibrutinib is a spray-dried ibrutinib compositioncomprising about 20% w/w of ibrutinib dispersed into a polymer matrix;and the polymer in the polymer matrix is hydroxypropyl methyl celluloseacetate succinate (HPMCAS).
 3. A solid dispersion formulation, whereinthe formulation comprises a) about 49 to about 51% w/w of 50% activespray-dried ibrutinib, wherein ibrutinib is a compound of formula (I),

b) about 16 to about 18% w/w of lactose, c) about 24 to about 26% w/w ofmicrocrystalline cellulose, d) about 5 to about 7% w/w of croscarmellosesodium, e) about 0.8 to about 1.2% w/w of colloidal silicon dioxide, andf) about 0.2 to about 0.8% w/w of magnesium stearate; and wherein the50% active spray-dried ibrutinib is a spray-dried ibrutinib compositioncomprising about 50% w/w of ibrutinib dispersed into a polymer matrix;and the polymer in the polymer matrix is polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®).
 4. A method fortreating a cancer comprising administering to a patient in need thereofa therapeutically effective amount of the solid dispersion formulationof claim 1, wherein the cancer is selected from chronic lymphocyticleukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma(MCL), and Waldenstrom macroglobulinemia.
 5. A method for treating acancer comprising administering to a patient in need thereof atherapeutically effective amount of the solid dispersion formulation ofclaim 2, wherein the cancer is selected from chronic lymphocyticleukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma(MCL), and Waldenstrom macroglobulinemia.
 6. A method for treating acancer comprising administering to a patient in need thereof atherapeutically effective amount of the solid dispersion formulation ofclaim 3, wherein the cancer is selected from chronic lymphocyticleukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma(MCL), and Waldenstrom macroglobulinemia.